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US 10,420,844 B2Granted
Peptide pharmaceuticals
AssigneeMederis Diabetes LLC
InventorJohn J. Nestor
Life of this patent
Estimating the term…
Abstract
Described herein are methods of syntheses and therapeutic uses of covalently modified peptides and/or proteins. The covalently modified peptides and/or proteins allow for improved pharmaceutical properties of peptide and protein-based therapeutics.
Claims22
A peptide product having the structure of:
- (SEQ. ID. NO. 172)
- aa1-aa2-aa3-aa4-aa5-aa6-aa7-aa8-aa9-aa10-aa11-
- aa12-aa13-aa14-aa15-aa16-aa17-aa18-aa19-aa20-aa21-
- aa22-aa23-aa24-aa25-aa26-aa27-aa28-aa29-aa30-aa31-
- aa32-aa33-aa34-aa35-aa36-Z FORMULA 2-V
- wherein:
- Z is —OH or NH—R3, wherein R3 is H, a substituted or unsubstituted C1-C12 alkyl, or a PEG chain of less than 10 Da;
- aa1 is Ala, Ser, Val, Pro, Aib, Ac5c, or Deg;
- aa2 is Val;
- aa3 is Ser, Ala, Aib, Ac4c, or Deg;
- aa4 is Glu;
- aa5 is His or Ile;
- aa6 is Gln or Cit;
- aa7 is Leu or Phe;
- aa8 is Leu, Met, or Nle;
- aa9 is His;
- aa10 is Asp, Asn, Gln, Glu, Cit, Ala, or Aib;
- aa11 is Lys, Leu, Ile, Arg, or hArg;
- aa12 is Gly, Ala, Glu, Lys, Aib, or Ac5c;
- aa13 is Lys or Arg;
- aa14 is Ser, His, Trp, Phe, Leu, Arg, Lys, Glu, Nal(2), or cyclized to position aa18;
- aa15 is Ile, Leu, or Aib;
- aa16 is Gln, Asn, Glu, Lys, Ser, Cit, Aib, Ac5c, or U(X);
- aa17 is Asp, Ser, Aib, Ac4c, Ac5c, or U(X);
- aa18 is absent or Leu, Gln, Cit, Aib, Ac5c, Lys, Glu, U(X), or cyclized to position aa14;
- aa19 is absent or Arg, Glu, Aib, Ac4c, Ac5c, or U(X);
- aa20 is absent or Arg, Glu, Lys, Aib, Ac4c, Ac5c, or U(X);
- aa21 is absent or Arg, Val, Aib, Ac5c, Deg, or U(X);
- aa22 is absent or Phe, Glu, Aib, Ac5c, Lys, U(X), or cyclized to position aa18 or aa26;
- aa23 is absent or Leu, Phe, Trp, or U(X);
- aa24 is absent or His, Arg, Leu, Aib, Ac5c, or U(X);
- aa25 is absent or His, Lys, Arg, or U(X);
- aa26 is absent or His, Lys, Arg, Aib, Ac5c, or cyclized to position aa22;
- aa27 is absent or Leu or Lys;
- aa28 is absent or Ile or Leu;
- aa29 is absent or Ala, Gln, Cit, or Aib;
- aa30 is absent or Glu, Asp, or Aib;
- aa31 is absent or Ile, Val, Aib, Ac5C, or U(X);
- aa32 is absent or His, Aib, Ac5C, or U(X);
- aa33 is absent or Thr, Asn, Aib, Ac5C, or U(X);
- aa34 is absent or Ala, Phe, Aib, Ac5C, or U(X);
- aa35 is absent or Aib, Ac5C, or U(X);
- aa36 is absent or Aib, Ac5C, or U(X);
- U is a linker amino acid;
- and
- X is a surfactant covalently attached to a linker amino acid U;
- wherein any two of aa1-aa36 are optionally cyclized through their side chains to form a lactam linkage;
- provided that one, or at least one, of aa16-aa25 and aa31-aa36 is a linker amino acid U covalently attached to a surfactant X;
- and
- wherein the surfactant X is a group of Formula 2-I:
- wherein:
- R1a is independently, at each occurrence, a bond, H, a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, or a steroid nucleus-containing moiety;
- R1b, R1c and R1d are each, independently at each occurrence, a bond, H, a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted alkoxyaryl group, or a substituted or unsubstituted aralkyl group;
- W1 is independently, at each occurrence, —CH2—, —CH2—O—, —(C═O)—, —(C═O)—O—, —(C═O)—NH—, —(C═S)—, —(C═S)—NH—, or —CH2—S—;
- W2 is —O—, —CH2— or —S—;
- R2 is independently, at each occurrence, a bond, a bond to U, H, a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, —NH2, —SH, C2-C4-alkene, C2-C4-alkyne, —NH(C═O)—CH2—Br, —(CH2)m-maleimide, or —N3,
- n is 1, 2 or 3;
- and
- m is 1-10.
56 more elements
A peptide product selected from:
- 1) Ac5c1-Val2-Aib3-Glu4Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-dodecyl beta-D-glucuronyl)18-NH2 (SEQ. ID. NO. 180);
- 2) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-alkyl beta-D-glucuronyl)18-Aib19-NH2, wherein alkyl is dodecyl, tetradecyl, hexadecyl or octadecyl (SEQ. ID. NO. 283);
- 3) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-alkyl beta-D-glucuronyl)18-Ac4c19-NH2, wherein alkyl is dodecyl, tetradecyl, hexadecyl or octadecyl (SEQ. ID. NO. 284);
- 4) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Glu*16-Aib17-Lys(N-epsilon-1′-alkyl beta-D-glucuronyl)18-Aib19-Lys*20-NH2, wherein Glu*16 and Lys*20 are linked through their sidechains to form a lactam and alkyl is dodecyl, tetradecyl, hexadecyl or octadecyl (SEQ. ID. NO. 285);
- 5) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Glu*12-Arg13-Trp14-Ile15-Lys*16-Aib17-Lys(N-epsilon-1′-alkyl beta-D-glucuronyl)18-Aib19-NH2, wherein Glu*12 and Lys*16 are linked through their sidechains to form a lactam and alkyl is dodecyl, tetradecyl, hexadecyl or octadecyl (SEQ. ID. NO. 286);
- 6) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Phe14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-alkyl beta-D-glucuronyl)18-Aib19-NH2, wherein alkyl is dodecyl, tetradecyl, hexadecyl or octadecyl (SEQ. ID. NO. 287);
- 7) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-alkyl beta-D-glucuronyl)18-Aib19-Aib20-NH2, wherein alkyl is dodecyl, tetradecyl, hexadecyl or octadecyl (SEQ. ID. NO. 288);
- 8) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Glu*12-Arg13-Trp14-Ile15-Lys*16-Aib17-Lys(N-epsilon-1′-alkyl beta-D-glucuronyl)18-Aib19-Aib20-NH2, wherein Glu*12 and Lys*16 are linked through their sidechains to form a lactam and alkyl is dodecyl, tetradecyl, hexadecyl or octadecyl (SEQ. ID. NO. 289);
- 9) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-dodecyl beta-D-glucuronyl)18-Aib19-NH2 (SEQ. ID. NO. 207);
- 10) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-tetradecyl beta-D-glucuronyl)18-Aib19-NH2 (SEQ. ID. NO. 260);
- 11) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-hexadecyl beta-D-glucuronyl)18-Aib19-NH2 (SEQ. ID. NO. 261);
- 12) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-octadecyl beta-D-glucuronyl)18-Aib19-NH2 (SEQ. ID. NO. 262);
- 13) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-dodecyl beta-D-glucuronyl)18-Aib19-Aib20-NH2 (SEQ. ID. NO. 275);
- 14) Ac5c1-Val2-Aib3-Glu4-Ile5-Gln6-Leu7-Nle8-His9-Gln10-hArg11-Ala12-Arg13-Trp14-Ile15-Gln16-Aib17-Lys(N-epsilon-1′-hexadecyl beta-D-glucuronyl)18-Aib19-Aib20-NH2 (SEQ. ID. NO. 277);
- peptide products designated EU-201 through EU-299 and EU-900 through EU-908 in Table 2 in FIG. 2;
- and
- pharmaceutically acceptable salts thereof.
14 more elements
Dependencies are inferred from the claim text.