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US 12,753,205 B2Granted
Peptide libraries with non-canonical amino acids
AssigneeRegeneron Pharmaceuticals, Inc.
InventorAnders Eliasen
Life of this patent
Estimating the term…
Abstract
Disclosed are peptides having non-canonical amino acids. These peptides are useful, for example, as protein binding agents. Libraries of such peptides can be used, for example to screen and select protein binding agents. The broader chemical space of the disclosed peptides can provide peptide with different, improved, more specific, and/or pharmaceutically compatible peptides and protein binding agents. In some forms, the peptides can have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R, R1, L1, L2, G, M, Y1 Y2 and SEQ are as defined herein. Methods associated with preparation and use of such peptides, as well as pharmaceutical compositions comprising such peptides, are also disclosed.
Claims29
A method for identifying a target binding compound, the method comprising:
- (A) providing a first peptide library comprising a plurality of first peptide library members, members of the first peptide library optionally comprising an alkyne, azide, reporter moiety, or combinations thereof;
- (B) contacting the first peptide library with a target or a truncated analogue thereof, the target or truncated analogue thereof comprising a first binding site and optionally an alkyne, azide, reporter moiety, or combinations thereof;
- (C) identifying a first peptide library member with affinity for the first binding site and optionally modifying the first peptide library member to include an alkyne or azide;
- (D) optionally providing a second peptide library comprising a plurality of second peptide library members, members of the second peptide library comprising an azide or alkyne;
- (E) optionally contacting the second peptide library with a composition comprising the target or truncated analogue thereof and the first peptide library member of step C;
- and
- (F) optionally forming a triazole-linked conjugate between the first peptide library member of step C and a second peptide library member, the second peptide library member having affinity for a second binding site on the target or truncated analogue thereof;
- wherein the first peptide library and/or the second peptide library comprise cyclic peptides comprising a sequence region and a linker region represented by Formula (I′):
- or a salt, tautomer, or stereoisomer thereof, wherein:
- (i) SEQ is the sequence region comprising a variable peptide sequence comprising from 2 to 20 amino acids selected from a set of amino acids, wherein the set of amino acids comprises a combination of canonical amino acids and non-canonical amino acids, wherein two or more of the amino acids in the set are non-canonical amino acids and four or more of the amino acids in the set are canonical amino acids;
- (ii) the linker region comprises:
- L1 and L2 are each independently optionally substituted alkylene linker moieties, wherein each alkylene linker moiety is optionally substituted with an α-amino carbonyl, a linkage to a solid support, a linkage to a reporter moiety, a linkage to a peptide ligand, a linkage to an azide or alkyne moiety, or combinations thereof;
- G is a triazole, a carbon-carbon double bond, or an amide;
- M is absent or methionine;
- R is H, -L3-A, or —C(═O)-L3-A;
- wherein L3 is an optionally substituted linker moiety, and wherein A is an alkyne, azide, or a bond to a peptide ligand;
- R1 is H or C1-C6 alkyl;
- y1 and y2 are each individually 0 or 1;
- and
- wherein the linker region is covalently linked via the amino and carboxy termini of the sequence region.
17 more elements
A method for identifying a target binding compound, the method comprising:
- (A) providing a first peptide library comprising a plurality of first peptide library members, members of the first peptide library optionally comprising an alkyne, azide, reporter moiety, or combinations thereof;
- (B) contacting the first peptide library with a target or a truncated analogue thereof, the target or truncated analogue thereof comprising a first binding site and optionally an alkyne, azide, reporter moiety, or combinations thereof;
- (C) identifying a first peptide library member with affinity for the first binding site and optionally modifying the first peptide library member to include an alkyne or azide;
- (D) optionally providing a second peptide library comprising a plurality of second peptide library members, members of the second peptide library comprising an azide or alkyne;
- (E) optionally contacting the second peptide library with a composition comprising the target or truncated analogue thereof and the first peptide library member of step C;
- and
- (F) optionally forming a triazole-linked conjugate between the first peptide library member of step C and a second peptide library member, the second peptide library member having affinity for a second binding site on the target or truncated analogue thereof;
- wherein the first peptide library and/or the second peptide library comprise cyclic peptides having a structure represented by Formula (I′b):
- or a salt, tautomer, or stereoisomer thereof, wherein:
- SEQ comprises a variable peptide sequence comprising from 2 to 20 amino acids selected from a set of amino acids, wherein the set of amino acids comprises a combination of canonical amino acids and non-canonical amino acids, wherein two or more of the amino acids in the set are non-canonical amino acids and four or more of the amino acids in the set are canonical amino acids;
- G is a triazole or a carbon-carbon double bond;
- R1 is H or C1-C6 alkyl;
- R3 is H, a linkage to a solid support, a linkage to an alkyne or azide moiety, or a linkage to a reporter moiety;
- R4 is H or C1-C6 alkyl;
- and
- x and y are each independently integers from 1 to 8.
13 more elements
A method for identifying a target binding compound, the method comprising:
- (A) providing a first peptide library comprising a plurality of first peptide library members, members of the first peptide library optionally comprising an alkyne, azide, reporter moiety, or combinations thereof;
- (B) contacting the first peptide library with a target or a truncated analogue thereof, the target or truncated analogue thereof comprising a first binding site and optionally an alkyne, azide, reporter moiety, or combinations thereof;
- (C) identifying a first peptide library member with affinity for the first binding site and optionally modifying the first peptide library member to include an alkyne or azide;
- (D) optionally providing a second peptide library comprising a plurality of second peptide library members, members of the second peptide library comprising an azide or alkyne;
- (E) optionally contacting the second peptide library with a composition comprising the target or truncated analogue thereof and the first peptide library member of step C;
- and
- (F) optionally forming a triazole-linked conjugate between the first peptide library member of step C and a second peptide library member, the second peptide library member having affinity for a second binding site on the target or truncated analogue thereof;
- wherein the first peptide library and/or the second peptide library comprise cyclic peptides having a structure according to any one of the following formulae:
- or a salt, tautomer, or stereoisomer thereof, wherein:
- SEQ comprises a variable peptide sequence comprising from 2 to 20 amino acids selected from a set of amino acids, wherein the set of amino acids comprises a combination of canonical amino acids and non-canonical amino acids, wherein two or more of the amino acids in the set are non-canonical amino acids and four or more of the amino acids in the set are canonical amino acids;
- and,
- R3 is H, a linkage to a solid support, a linkage to an alkyne or azide moiety, or a linkage to a reporter moiety.
9 more elements
Dependencies are inferred from the claim text.