US 2026/0306644 A1 · ANTIBODY RECRUITING MOLECULES FOR THE TREATMENT OF CORONAVIRUS DISEASE-19

Abstract

The present disclosure describes a compound or antibody recruiting molecule (ARM), or a pharmaceutically acceptable salt thereof, having one or more antibody binding moiety (ABM) that binds to one or more antibodies or fragments thereof, one or more target binding moiety (TBM) that binds the spike glycoprotein of a coronavirus (e.g., severe acute respiratory syndrome coronavirus 2), and optionally a linker moiety (L) that covalently links the one or more ABMs and the one or more TBMs. Further described are methods of making and using the compounds of the present disclosure.

Claims37

Dependent claims

A compound or antibody recruiting molecule (ARM), or a pharmaceutically acceptable salt thereof, having the chemical structure:

where
(ABM) is an antibody binding moiety or an antibody binding terminus (ABT)) that binds to one or more antibodies or fragments thereof,
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1, 2, or 3, preferably 1);
(TBM) is a target binding moiety or target binding terminus (TBT)) that binds the spike glycoprotein of a coronavirus (e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)),
b is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1, 2, or 3, preferably 1);
and
L is an optional a linker moiety (L) that covalently links the one or more ABMs and the one or more TBMs.

4 more elements

The compound of claim 4, wherein

the N-terminus of the ABM, the TBM, or both are acetylated (—COCH3);
the C-terminus of the ABM, the TBM, or both are amidated (—NH2);
or a combination thereof
(C) The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each TBM or target binding moiety independently is or comprises (A), (B), or (CA) an amino acid sequence XT1-XT59:
XT1XT2XT3XT4XT5XT6XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40XT41XT42XT43XT44XT45XT46XT47XT48XT49XT50X51XT52XT53XT54XT55XT56XT57XT58XT59, wherein:
each of XT1 through XT59 is an independently selected amino acid residue;
and
optionally one or more of XT1XT10, or one or more of XT28-XT59 are absent, optionally the XT1-XT59 sequence comprises 1, 2, 3 or 4 additional amino acids bound at any point between XT1 and XT59 where no more than 2 of the additional amino acid are consecutive;
when XT1-XT5 are absent, then XT11-XT40 are present;
when XT28-XT59 are absent, then XT1-XT10 are present;
XT1 is absent or a hydrophobic amino acid (e.g., an amino acid residue that has a hydrophobic side chain), such as Ala/A, Aib, or an isosterically equivalent amino acid;
XT2 is absent or a polar uncharged amino acid (e.g., an amino acid residue with a polar uncharged side chain, such as at physiological pH about 7.4), such as Ser/S or an isosterically equivalent amino acid;
XT3 is
absent,
a negatively charged amino acid (e.g., an amino acid residue with a negatively charged side chain, such as at physiological pH about 7.4), such as Asp/D, D-Asp/dD, or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT4 is
Absent,
a positively charged amino acid (e.g., an amino acid residue with a positively charged side chain, such as at physiological pH of about 7.4), such as Lys/K or an isosterically equivalent amino acid;
or
a hydrophobic amino acid, such as Abu, or an isosterically equivalent amino acid;
XT5 is absent or a negatively charges amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT6 is absent or a hydrophobic amino acid, such as Trp/W or an isosterically equivalent amino acid;
XT7 is absent or a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is absent or a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is absent or a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is absent or a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I, d-Ile/dI, or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is absent or a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a Pro/P or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT28 is absent or a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is absent or a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT30 is absent or a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT31 is
Absent,
a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT32 is absent or a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is absent or hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is absent or a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is absent or a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
absent,
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is absent or a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT31 is absent or a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is absent or a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
absent,
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid;
XT41 is absent or an uncharged, non-polar amino acid, such as Gly/G, Ala/A, D-Ala/dA, Phe/F, D-Phe/dF, or an isosterically equivalent amino acid;
XT42 is absent or a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT43 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT44 is absent or a positively charged amino acid, such as R or an isosterically equivalent amino acid;
XT45 is absent or a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT46 is absent or a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT47 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT48 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT49 is absent or a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT50 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT51 is absent or a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT52 is absent or a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT53 is absent or a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT54 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT55 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT56 is absent or a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT57 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT58 is
absent,
a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT59 is absent or a hydrophobic amino acid, such as 2-(methylamino)propanoic acid, Aib, or an isosterically equivalent amino acid;
optionally two amino acid residues of the TBM are covalently linked (e.g., two Cys/S amino acid residues form a disulfide bond) to form a cyclic structure;
or
a combination thereof,
(B) an amino acid sequence XT1a-XT64a:
XT1aXT2aXT3aXT4aXT5aXT6aXT7aXT8aXT9aXT10aXT11aXT12aXT13aXT14aXT15aXT16aXT17aXT118aXT19aXT20aXT21aXT22aXT23aXT24aXT25aXT26aXT27aXT28aXT29aXT30aXT31aXT32aXT33aXT34aXT35aXT36aXT37aXT38aXT39aXT40aXT41aXT42aXT43aXT44aXT45aXT46aXT47aXT48aXT49aXT50aXT51aXT52aXT53aXT54a XT55aXT56aXT57aXT58aXT59aXT60aXT61aXT62aXT63aXT64a, wherein:
each of XT1a through XT64a is an independently selected amino acid residue), optionally the XT1a-XT64a sequence comprises 1, 2, 3 or 4 additional amino acids bound at any point between XT1a and XT64awhere no more than 2 of the additional amino acid are consecutive wherein:
XT1a is an uncharged, polar amino acid, such as Asn/N or an isosterically equivalent amino acid;
XT2a is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT3a is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT4a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT5a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT6a is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT7a is a hydrophobic amino acid, such as Met/M or an isosterically equivalent amino acid;
XT8a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9a is a hydrophobic amino acid, such as Met/M or an isosterically equivalent amino acid;
XT10a is a hydrophobic amino acid, such as Tyr/T or an isosterically equivalent amino acid;
XT11a is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT12a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT13a is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT14a is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT15a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT16a is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT17a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18a is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT19a is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT20a is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT21a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT22a is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT23a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT24a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT25a is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT26a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT27a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT28a is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT29a is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT30a is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT31a is an uncharged, polar amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT32a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT33a is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT34a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT35a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT36a is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT37a is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT38a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT39a is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT40a is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT41a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT42a is an uncharged, polar amino acid, such as Asn/N or an isosterically equivalent amino acid;
XT43a is an uncharged, polar amino acid, such as Asn/N or an isosterically equivalent amino acid;
XT44a is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT45a is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT46a is an uncharged, polar amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT47a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT48a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT49a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT50a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT51a is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT52a is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT53a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT54a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT55a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT56a is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT57a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT58a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT59a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT60a is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT61a is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT62a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT63a is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT64a is an uncharged, polar amino acid, such as Ser/S or an isosterically equivalent amino acid;
or a combination thereof, or
(C) an amino acid sequence XT1-XT40:
XT1XT2XT3XT4XT5XT6XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40 wherein:
each of XT1 through XT40 is an independently selected amino acid residue;
two amino acid residues of the TBM are covalently linked (e.g., two Cys/S amino acid residues form a disulfide bond) to form a cyclic structure;
and
either XT15 and XT30 are Cys/S covalently linked with a disulfide bond or XT18 and XT27 are Cys/S covalently linked with a disulfide bond;
optionally one or more of XT1 to XT8 are absent, and
optionally the XT1-XT40 sequence comprises 1, 2, 3 or 4 additional amino acids bound at any point between XT1 and XT40 where no more than 2 of the additional amino acid are consecutive,
wherein:
XT1 is absent or a hydrophobic amino acid, such as Ala/A, Aib, or an isosterically equivalent amino acid;
XT2 is absent or a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid;
XT3 is
absent,
a negatively charged amino acid, such as Asp/D, D-Asp/dD, or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT4 is absent or a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT5 is absent or a negatively charges amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT6 is absent or a hydrophobic amino acid, such as Trp/W or an isosterically equivalent amino acid;
XT7 is absent or a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is absent or a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT15 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid, which Cys/C is bound via a disulfide bond to XT30;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid, which Cys/S is bound via a disulfide bond to XT27;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or a Cys/C which is bound to XT18 via a disulfide bond;
XT28 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT50 is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid, or a Cys/C which is bound to XT15 via a disulfide bound;
XT31 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid;
XT132 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is absent or a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT38 is absent or a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is absent or a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
absent,
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid.

218 more elements

The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein each TBM independently is or includes

(a) XT1XT2XT3XT4XT5XT6XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40 XT41XT42XT43XT44XT45XT46XT47XT48XT49XT50XT51XT52XT53XT54XT55XT56XT57XT58XT59, wherein:
XT1 is absent or a hydrophobic amino acid, such as Ala/A, Aib, or an isosterically equivalent amino acid;
XT2 is absent or a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid;
XT3 is
a negatively charged amino acid, such as Asp/D, D-Asp/dD, or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT4 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT5 is a negatively charges amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT6 is a hydrophobic amino acid, such as Trp/W or an isosterically equivalent amino acid;
XT7 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I, d-Ile/dI or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a Pro/P or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT28 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT30 is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT31 is
a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT132 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT31 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid;
XT41 is an uncharged, non-polar amino acid, such as Gly/G, Ala/A, D-Ala/dA, Phe/F, D-Phe/dF, or an isosterically equivalent amino acid;
XT42 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT43 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT44 is a positively charged amino acid, such as R or an isosterically equivalent amino acid;
XT45 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT46 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT47 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT48 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT49 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT10 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT11 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT52 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT53 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT54 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT55 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT56 is absent or a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT57 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT58 is
absent,
a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT59 is absent or a hydrophobic amino acid, such as 2-(methylamino)propanoic acid, Aib, or an isosterically equivalent amino acid;
(b) XT1XT2XT3XT4XT5XT6XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40XT41, wherein:
at least two amino acid residues of the TBM are covalently linked (e.g., two Cys/S amino acid residues form a disulfide bond) to form a cyclic structure,
XT15 and XT30 are Cys/S covalently linked with a disulfide bond and/or XT18 and XT27 are Cys/S covalently linked with a disulfide bond:
XT1 is absent or a hydrophobic amino acid, such as Ala/A, Aib, or an isosterically equivalent amino acid;
XT2 is absent or a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid;
XT3 is
a negatively charged amino acid, such as Asp/D, D-Asp/dD, or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT4 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT5 is a negatively charges amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT6 is a hydrophobic amino acid, such as Trp/W or an isosterically equivalent amino acid;
XT7 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT15 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid, or a Cys/C, which Cys/C can be bound via a disulfide bond to XT30;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid, or a Cys/C, which Cys/S can be bound via a disulfide bond to XT27;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or a Pro/P or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or a Cys/C, which can be bound to XT18 via a disulfide bond;
XT28 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT30 is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid, or a Cys/C, which can be bound to XT15 via a disulfide bound;
XT31 is
a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT32 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT38 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid;
XT41 is absent or an uncharged, non-polar amino acid, such as Gly/G, Ala/A, D-Ala/dA, Phe/F, D-Phe/dF, or an isosterically equivalent amino acid;
(c) I XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40 XT41XT42XT43XT44XT45XT46XT47XT48XT49XT50XT51XT52XT53XT54XT55XT56XT57XT58XT59, wherein:
XT7 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT15 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a Pro/P or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT28 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT30 is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT31 is
a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT32 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT31 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid;
XT41 is an uncharged, non-polar amino acid, such as Gly/G, Ala/A, D-Ala/dA, Phe/F, D-Phe/dF, or an isosterically equivalent amino acid;
XT42 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT43 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT44 is a positively charged amino acid, such as R or an isosterically equivalent amino acid;
XT45 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT46 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT47 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT48 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT49 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT10 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT51 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT52 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT53 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT54 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT55 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT56 is absent or a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT57 is absent or a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT58 is
absent,
a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT59 is absent or a hydrophobic amino acid, such as 2-(methylamino)propanoic acid, Ala/A, or an isosterically equivalent amino acid;
(d) XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40XT41, wherein:
XT7 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT15 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or a Pro/P or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT28 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT30 is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT31 is
a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT32 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT31 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid;
XT41 is an uncharged, non-polar amino acid, such as Gly/G, Ala/A, D-Ala/dA, Phe/F, D-Phe/dF, or an isosterically equivalent amino acid;
(e)XT1XT2XT3XT4XT5XT6XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40XT41 wherein:
XT1 is absent or a hydrophobic amino acid, such as Ala/A, Aib, or an isosterically equivalent amino acid;
XT2 is absent or a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid;
XT3 is
a negatively charged amino acid, such as Asp/D, D-Asp/dD, or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT4 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT5 is a negatively charges amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT6 is a hydrophobic amino acid, such as Trp/W or an isosterically equivalent amino acid;
XT7 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT15 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a Pro/P or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT28 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT30 is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid;
XT31 is
a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT32 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT38 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid;
XT41 is an uncharged, non-polar amino acid, such as Gly/G, Ala/A, D-Ala/dA, Phe/F, D-Phe/dF, or an isosterically equivalent amino acid;
optionally XT18 and XT27 form a disulfide bond;
or
a combination thereof, or
(f)XT1XT2XT3XT4XT5XT6XT7XT8XT9XT10XT11XT12XT13XT14XT15XT16XT17XT18XT19XT20XT21XT22XT23XT24XT25XT26XT27XT28XT29XT30XT31XT32XT33XT34XT35XT36XT37XT38XT39XT40XT41 wherein:
XT1 is absent or a hydrophobic amino acid, such as Ala/A, Aib, or an isosterically equivalent amino acid;
XT2 is absent or a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid;
XT3 is
a negatively charged amino acid, such as Asp/D, D-Asp/dD, or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Ala/A, D-Ala/dA, or an isosterically equivalent amino acid;
XT4 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT5 is a negatively charges amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT6 is a hydrophobic amino acid, such as Trp/W or an isosterically equivalent amino acid;
XT7 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT8 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT9 is a polar uncharged amino acid, such as Gln/Q or an isosterically equivalent amino acid;
XT10 is a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT11 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT12 is a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT13 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT14 is a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT15 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT16 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT17 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT18 is a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT19 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT20 is a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT21 is a hydrophobic amino acid, such as Leu/L, norleucine/Nle, or an isosterically equivalent amino acid;
XT22 is
an uncharged, non-polar amino acid, such as Gly/G or an isosterically equivalent amino acid, or
a positively charged amino acid, such as His/H, D-His/dH, or an isosterically equivalent amino acid;
XT23 is a positively charged amino acid, such as His/H or an isosterically equivalent amino acid;
XT24 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT25 is
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a Pro/P or an isosterically equivalent amino acid;
XT26 is a hydrophobic amino acid, such as Ala/A or an isosterically equivalent amino acid;
XT27 is a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid;
XT28 is a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT29 is a positively charged amino acid, such as Arg/R or an isosterically equivalent amino acid;
XT30 is a hydrophobic amino acid, such as Val/V or an isosterically equivalent amino acid, or a Cys/C or an isosterically equivalent amino acid;
XT31 is
a polar uncharged amino acid, such as Ser/S or an isosterically equivalent amino acid, or
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid;
XT32 is a negatively charged amino acid, such as Asp/D or an isosterically equivalent amino acid;
XT33 is absent or a hydrophobic amino acid, such as Leu/L or an isosterically equivalent amino acid;
XT34 is absent or a hydrophobic amino acid, such as Ile/I or an isosterically equivalent amino acid;
XT35 is absent or a hydrophobic amino acid, such as Tyr/Y or an isosterically equivalent amino acid;
XT36 is
absent,
a negatively charged amino acid, such as Glu/E or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala/A, or an isosterically equivalent amino acid;
XT37 is absent or a hydrophobic amino acid, such as Phe/F or an isosterically equivalent amino acid;
XT31 is absent or a hydrophobic amino acid, such as Met/M, norleucine/Nle, or an isosterically equivalent amino acid;
XT39 is absent or a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid;
XT40 is
absent,
a positively charged amino acid, such as Lys/K or an isosterically equivalent amino acid, or
a hydrophobic amino acid, such as Aib, Ala, or a sterically equivalent amino acid;
XT41 is absent or an uncharged, non-polar amino acid, such as Gly/G, Ala/A, D-Ala/dA, Phe/F, D-Phe/dF, or an isosterically equivalent amino acid;
optionally XT15 and XT30 form a disulfide bond;
or
a combination thereof.

355 more elements

The compound of any one of claims 1-7, wherein one or more TBM, independently, is or comprises a TBM from an exemplary compound of the present disclosure, such as an optionally substituted amino acid sequence independently selected from:

DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER,
DCAWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER,
DKEWILQKIYEIMRLLDELGHAPASMRVSDLIYEFMKKGDERLLEEAERLLEEVER,
DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKG,
DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK,
DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYE,
DKEWILQKIYEIMRLLDELGHAPASMRVER,
DKEWILQKIYEIMRLLDELGHAEASMRVS,
DKEWILQKIYEIMRLLDELGHAEAS,
DKEWILQKIYEIMRLLDELG,
ILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKG,
IYEIMRLLDELGHAEASMRVSDLIYEFMKKG,
ILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK,
[Aib]DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKG,
[Aib]SDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK[dA],
[Aib]SDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK[dF],
D[Abu]EWILQKIYEIMRLLDELG,
[Aib]SDKEWILQKIYEI[Nle]RLLDELGHAE,
[Aib]SDKEWILQLIYEIMRLLDELGHAEASMRVSDLIYEFMKK[dA],
[Aib]SDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK[dF],
[Aib]SDKEWILQKIYEIMRLLDELGHAEAS[Nle]RVSDLIY[Aib]FMK[Aib]G,
DKEWILQKIYEIMRLLDEL[DHis]HAPASMRVSDLIYEFMKKGDERLLEEAERLLEEVER,
DKEWILQLIYEI[Nle]RLLDELGHAEASMRVSDLIYEF[Nle]KKGDERLLEEAERLLEEVER,
DKEWILQKIYEIMRLLDE[Nle][DHis]HAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER,
DKEWILQKIYEIMRLLDE[Nle][DHis]HAEASMRVSDLIYEFMKKG,
DKEWILQKIYE[d]]MRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER,
DKEWILQKIYEIMRLLDEL[DHis]HAPASM RVSDLIYEFMKKGDERLLEEAERLLEEVER,
[Aib]SDKEWILQKIYEI[Nle]RLLDELGHAEASM
RVSDLIYEHMKKGDERLLEEAERLLE[Aib]VER[Aib],
[Aib]SDKEWILQKIYEIMRLLDELGHAEAS[Nle]RVSDLIY[Aib]FMK[Aib]G,
[Aib]SDKEWILQKIYEI[Nle]RLLDELGHAEAS[Nle]RVSDLIY[Aib]FMK[Aib]G,
SDKEWILQKIYEIMRLLDELGHAPASMRVSDLIYEFMKKG,
DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVE[DAla],
DKEWILQKIYEIMRLLDELGHAPASMRVSDLIYEFMKKGDERLLEEAERLLEEVE[DAla],
DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVEA[2-
(methylamino)propanoic acid],
[DAla]KEWILQKIYEIMRLLDELGHAPASMRVSDLIYEFMKKGDERLLEEAERLLEEVER,
SDKEWILQKIYEIMRL-Cyclo[CDELGHAEAC]MRVSDLIYEFMKKG,
DKEWILQKIYEIMRL-Cyclo[CDELGHAEAC]-MRVSDLIYEFMKKG
ILQKIYEIMRL-Cyclo[CDELGHAEAC]-MRVSDLIYEFMKKG,
QKIYEIMRL-Cyclo[CDELGHAEAC]-MRVSDLIYEFMKKG,
DKEWILQKIYEIMRL-Cyclo[CDELGHAEAC]MRVSDLIYEFMKK,
DKEWILQKIYEI-Cyclo[CRLLDELGHAEASMRC]-SDLIYEFMKKG,
ILQKIYEI-Cyclo[CRLLDELGHAEASMRC]-SDLIYEFMKKG,
or
QKIYEI-Cyclo[CRLLDELGHAEASMRC]-SDLIYEFMKKG.

43 more elements

The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein:

the ABM is a universal antibody binding moiety;
the ABM can bind to a Fab region of an antibody, a Fc region of an antibody, a Fc region bound to an Fc receptor, or two or more antibodies (e.g., 2, 3, 4, or more antibodies) that have different Fab regions;
or
a combination thereof.

1 more element

The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each ABM or universal antibody binding moiety is independently selected from:

wherein:
each Xaa is an independently selected amino acid residue (such as, a natural/proteinogenic amino acid, a unnatural/non-proteinogenic amino acid, or a combination thereof);
t is an integer from 0 to 50 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 59, or 50);
z is an integer from 3 to 50 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 59, or 50);
each Rc is independently -La-R′;
each La is independently a covalent bond, or an optionally substituted bivalent group selected C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with —C(R′)2-, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
each -Cy- is independently an optionally substituted bivalent group selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;
each R′ is independently —R, —C(O)R, —CO2R, or —SO2R;
each R is independently —H, or an optionally substituted group selected from C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30 aryl, C1-30 arylaliphatic, C1-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or
two R groups are optionally and independently taken together to form a covalent bond, or:
two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;
or
two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

10 more elements

The compound of any one of claims 1-10, wherein:

(a) one or more -(Xaa)z-, independently, is or comprises [X1]p1[X2]p2-X3X4X5X6X7X8X9X10X11X12-[X13]p13[X14]p14[X15]p15[X16]p16,
wherein:
each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 is an independently selected amino acid residue (e.g., of an amino acid of formula NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COOH), and
each of p1, p2, p13, p14, p15 and p16 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
(b) one or more -(Xaa)z-, independently, is or comprises —X3X4X5X6X7X8X9X10X11X12-, wherein:
each of X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 is independently an amino acid residue;
X6 is XaaA or XaaP;
X9 is XaaN;
and
X12 is XaaA or XaaP;
(c) one or more -(Xaa)z-, independently, is or comprises —X3X4X5X6X7X8X9X10X11X12-, wherein:
each of X3, X4, X5, X6, X7, X8, X9X10, X11, and X12 is an independently selected amino acid residue;
at least two amino acid residues are connected through one or more linkages of L;
Lb is an optionally substituted bivalent group selected C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with —C(R′)2-, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms;
X6 is XaaA or XaaP;
X9 is XaaN;
and
X12 is XaaA or XaaP;
(d) one or more -(Xaa)z-, independently, is or comprises —X2X3X4X5X6X7X8X9X10X11X12-, wherein:
each of X2, X3, X4, X5, X6, X7, X8, X9, X1, X11, and X12 is an independently selected amino acid residue;
at least two amino acid residues are connected through one or more linkages of L;
Lb is an optionally substituted bivalent group selected C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with —C(R′)2-, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms;
X4 is XaaA;
X5 is XaaA or XaaP;
X8 is XaaN;
and
X11 is XaaA;
(e) one or more -(Xaa)z-, independently, is or comprises —X2X3X4X5X6X7X8X9X10X11X12-, wherein:
each of X2, X3, X4, X5, X6, X7, X8, X9, X1, X11, and X12 is an independently selected amino acid residue;
at least two amino acid residues are connected through one or more linkages of L;
Lb is an optionally substituted bivalent group selected from C1-C20 aliphatic and C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with —C(R′)2-, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms;
X5 is XaaA or XaaP;
X8 is XaaN;
and
X11 is XaaA;
(f) one or more, -(Xaa)z-, independently, is or comprises —X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16-, wherein:
each of X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, and X16 is an independently selected amino acid residue;
at least two amino acid residues are connected through a linkage of Lb;
Lb is an optionally substituted bivalent group selected from C1-C20 aliphatic and C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with —C(R′)2-, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms;
X3 is XaaN;
X6 is XaaA;
X7 is XaaA or XaaP;
X9 is XaaN;
and
X13 is XaaA;
or
(g) a combination thereof,
wherein
XaaA is an amino acid residue (e.g., a residue of an amino acid of formula NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COOH) that has a side chain comprising an aromatic group (“aromatic amino acid residue”);
XaaP is an amino acid residue (e.g., a residue of an amino acid of formula NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COOH) that has a positively charged side chain (e.g., at physiological pH of about 7.4, “positively charged amino acid residue”);
and
XaaN is an amino acid residue (e.g., a residue of an amino acid of formula NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COOH) that has a negatively charged side chain (e.g., at physiological pH about 7.4, “negatively charged amino acid residue”).

49 more elements

The compound of claim 11, wherein (b) one or more -(Xaa)z-, independently, is or comprises —X3X4X5X6X7X8X9X10X11X12-, wherein:

each of X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 is an independently an amino acid of formula NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COOH as described in the present disclosure;
X3 is Lys;
X4 is Pro;
X5 is XaaA or XaaP, such as an amino acid residue whose side chain comprises an optionally substituted saturated, partially saturated or aromatic ring (e.g.,
X6 is His;
X8 is Gly;
X9 is Asp or Glu;
each of X7, X10, and X11 is independently an amino acid residue with a hydrophobic side chain (“hydrophobic amino acid residue”, XaaH) (such as X7 is
or Val, X10 is Met or
X11 is
or a combination thereof);
X12 is
optionally the —COOH of X12 forms an amide bond with the side chain amino group of Lys (X3), and the other amino group of the Lys (X3) is connected to a linker moiety and then a target binding moiety;
or
a combination thereof.

12 more elements

The compound of claim 13, wherein

Lb is an optionally substituted
or an optionally substituted
Lb connects two alpha-carbon atoms of two different amino acid residues;
both X5 and X10 are Cys, and the two —SH groups of their side chains form —S—S— (e.g., Lb is —CH2—S—S—CH2—);
or
a combination thereof.

3 more elements

The compound of any one of claims 1-18, wherein the amino acid has the structure:

NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COOH or N(Ra1)-La1-C(Ra2)(Ra3)-La2-CO-, or a pharmaceutically acceptable salt thereof, wherein:
each Ra1, R2, and Ra3 is independently -La-R′;
each La1and La2 is independently La;
each La is independently a covalent bond, or an optionally substituted bivalent group selected from C1-C20 aliphatic and C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the bivalent group are optionally and independently replaced with —C(R′)2-, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
each -Cy- is independently an optionally substituted bivalent group selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
each R′ is independently —R, —C(O)R, —CO2R, or —SO2R;
each R is independently —H, or an optionally substituted group selected from C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms, C1-30 aryl, C1-30 arylaliphatic, C1-30 arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1-10 heteroatoms, or
two R groups are optionally and independently taken together to form a covalent bond, or:
two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms;
or
two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms,
wherein each heteroatom of the amino acid is independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

9 more elements

The compounds of any one of claims 9-19, wherein two or more side chains of the amino acid residues (e.g., Ra2 or Ra3 of one amino acid residue with Ra2 or Ra3 of another amino acid residue) are take together to form a bridge (e.g., two cysteine residues in a ABM or a TBT form a —S—S— bridge as typically observed in natural proteins),

The compound of claim 20, wherein the bridge has the structure Lb, wherein:

each Lb is independently an optionally substituted bivalent group selected from C1-C20 aliphatic and C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with —C(R′)2-, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—;
each R′ is independently —R, —C(O)R, —CO2R, or —SO2R;
each R is independently —H, or an optionally substituted group selected from C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms, C1-30 aryl, C1-30 arylaliphatic, C1-30 arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1-10 heteroatoms, or
two R groups are optionally and independently taken together to form a covalent bond, or
two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;
or
two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;
and
each heteroatom of Lb is independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

6 more elements

The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein

(a) one or more ABM, independently, is or comprises an amino acid sequence selected from APAR, PARA, HWRGWA, WGRR, RRGW, NRFRGKYK, NARKFYK, RHRFNKD, TY, TYK, RTY, RTYK, PAM, WHL, ELVW, AWHLGELVW, DCAWHLGELVWCT, D-Cyclo[CAWHLGELVWC]T, DpLpAWHLGELVW, DpLpDCAWHLGELVWCT, CDCAWHLGELVWCTC, Ac-ASYHLGELVW[1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid][Aib]C, Cyclo[Ac-ASYHLGELVW[1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid][Aib]C], Ac-ASYHLGELVW[1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid][Aib]C[dE], Cyclo[Ac-ASYHLGELVW[1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid][Aib]C][dE], Ac-ASYHLGELVW[1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid][Aib]CE, and Cyclo[Ac-ASYHLGELVW[1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid][Aib]C]E;
(b) one or more ABM is an antibody binding moiety independently selected from Fc-III, Fc-III-4c, FcRM, FcBP-1, FcBP-2, FcRM, and PAM;
or
(c) a combination thereof.

1 more element

The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein the L is an optionally substituted C1-C70 alkylene group, an optionally substituted C1-C60 alkylene group, or an optionally substituted C1-C50 alkylene group (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, or C70 alkylene), wherein:

the L optionally comprises one to fourteen -C1-25 alkynelene-ABM covalently linked to the C1-70 alkynelene group;
and
the L optionally comprises one to fourteen -C1-25 alkynelene-TBM covalently linked to the C1-70 alkynelene group;
each CH2 group is optionally replaced with a group independently selected from CRL1RL2, O, S, SO, SO2, NH, CO, CH═CH, C≡C, 5-7 membered heterocyle, and 3-8 membered carbocycle;
each RL1 is independently selected from H, an amino acid side chain, or an optionally substituted linear or branched C1-5 alkyl with one or two CH2 groups are optionally replaced with a group independently selected from O, S, SO, SO2, or NH, wherein the C1-5 alkyl group is optionally substituted with a hydroxyl, —NH2, —NH3, oxo (═O), an optionally substituted 5-7 membered carbocycle or aryl, or an optionally substituted 3-10 membered heterocycle or heteroaryl;
each RL2 is independently selected from H and optionally substituted linear or branched C1-4 alkyl (e.g., methyl);
one or two CH2 groups of the C1-50 alkylene, the C1-25 alkylene-ABM, the C1-25 alkylene-TBM, or a combination thereof is optionally replaced with a [CON], wherein the [CON] is a bond or an optional chemical moiety that forms from a reaction production;
the L is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) groups independently selected from H, halogen, hydroxyl, cyano, oxo (═O), amino, imino (═NH), —COOH, C1-4 alkyl, C1-4haloalkyl, and C1-4alkoxy.

5 more elements

The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein each [CON], independently, is or comprises:

wherein:
each Y1 is independently CH2, O, S, NRL5 (e.g. NC1-C3alkyl)), C(O), S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
each Y2 is independently O, S, or NRL5;
each RL5 is independently H, C1-C3 alkyl, C1-C3 alkanoyl, or —C(O)(C1-C3alkyl) group;
each RL6 is independently H or C1-C3 alkyl group (preferably H);
and
RL3 and RL4 are each independently H, methyl, a bond (e.g., for attachment to ABM, L, or TBM);
or a dioxo or diamide group according to the structure:
(e.g., one end is for attachment to ABM, L, or TBM), wherein each RL7 is independently H or a C1-3 alkyl group (preferably H);
and n of [CON] is an integer from 1 to 10 (n is preferably 1, 2, 3, 4, 5, or 6).

7 more elements

Dependencies are inferred from the claim text.

Antibody recruiting molecules for the treatment of coronavirus disease-19

Life of this patent

Antibody recruiting molecules for the treatment of coronavirus disease-19

Life of this patent

Abstract

Claims37