US2020277351A1PendingUtilityA1
Peptide pharmaceuticals for insulin resistance
Est. expiryMay 28, 2034(~7.9 yrs left)· nominal 20-yr term from priority
Inventors:John J. Nestor
A61P 9/00Y02P20/55C07K 19/00C07H 13/12C07H 13/06A61K 47/549A61P 9/10C07K 14/605A61P 3/08A61K 47/64A61P 3/10A61P 9/12A61K 38/00A61P 31/10A61K 38/26A61P 3/04
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Claims
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.
Claims
exact text as granted — not AI-modified1 . A peptide product comprising a surfactant X, covalently attached to a peptide, the peptide comprising a linker amino acid U and at least one other amino acid:
wherein the surfactant X is a group of Formula I:
wherein:
R 1a is independently, at each occurrence, a bond, H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, or a steroid nucleus containing moiety;
R 1b , R 1c , and R 1d are each, independently at each occurrence, a protecting group, a saccharide, a bond, H, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted alkoxyaryl group, or a substituted or unsubstituted aralkyl group;
W 1 is independently, at each occurrence, —CH 2 —, —CH 2 —O—, —(C═O), —(C═O)—O—, —(C═O)—NH—, —(C═S)—, —(C═S)—NH—, or —CH 2 —S—;
W 2 is —O—, —CH 2 — or —S—;
R 2 is independently, at each occurrence, a bond to U, H, a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted alkoxyaryl group, or a substituted or unsubstituted aralkyl group, —NH—, —S—, -triazolo-, —NH(C═O)—CH 2 —, —(CH 2 ) m -maleimide-;
n is 1, 2 or 3; and
m is an integer of 1-10;
the peptide is selected from Formula II:
(SEQ. ID. NO. 1)
aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -aa 6 -aa 7 -aa 8 -aa 9 -aa 10 -aa 11 -
aa 12 -aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -aa 20 -
aa 21 -aa 22 -aa 23 -aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -aa 29 -
aa 30 -aa 31 -aa 32 -aa 33 -aa 34 -aa 35 -aa 36 -aa 37 -Z
Formula II
wherein:
Z is OH, N—R 4 -His, or —NH—R 3 ,
wherein
R 3 is H, substituted or unsubstituted C 1 -C 12 alkyl, or a PEG chain of less than 10 Da;
R 4 is a C 2 -C 10 acyl group, for example Ac or Bz;
aa 1 is His, N—R 4 -His, pGlu-His, or N—R 3 -His;
aa 2 is Ser, D-Ser, Ala, Gly, Pro, MePro, Aib, Ac4c, or Ac5c;
aa 3 is Gln or Cit;
aa 4 is Gly or D-Ala;
aa 5 is Thr or Ser;
aa 6 is Phe, Trp, 2FPhe, MePhe, 2FMePhe, or Nal2;
aa 7 is Thr or Ser;
aa 8 is Ser or Asp;
aa 9 is Asp or Glu;
aa 10 is Tyr, Leu, Met, Nal2, Bip, Bip2EtMeO, or U;
aa 11 is absent or Ser, Asn, Bip, or U;
aa 12 is absent or Lys, Glu, Ser, Arg, or U;
aa 13 is absent or Tyr, Gln, Cit, or U;
aa 14 is absent or Leu, Met, Nle, or U;
aa 15 is absent or Asp, Glu, or U;
aa 16 is absent or Ser, Gly, Glu, Ala, Aib, Ac5c, Lys, Arg, or U;
aa 17 is absent or Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, Lys, or U;
aa 18 is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U;
aa 19 is absent or Ala, Val, Aib, Ac4c, Ac5c, or U;
aa 20 is absent or Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U;
aa 21 is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U;
aa 22 is absent or Phe, Trp, Nal2, Aib, Ac4c, Ac5c, or U;
aa 23 is absent or Val, Ile, Aib, Ac4c, Ac5c, or U;
aa 24 is absent or Ala, Gln, Glu, Cit, or U;
aa 25 is absent or Trp, Nal2, or U;
aa 26 is Leu;
aa 27 is Leu;
aa 28 is Gln;
aa 29 is Thr;
aa 30 is absent or Lys, Aib, Ac4c, Ac5c, Arg, or U;
aa 31 is absent or Arg, Aib, Ac4c, Ac5c, or U;
aa 32 is absent or Asn, Aib, Ac4c, Ac5c, or U;
aa 33 is absent or Arg, Aib, Ac4c, Ac5c, or U;
aa 34 is absent or Asn, Aib, Ac4c, Ac5c, or U;
aa 35 is absent or Asn, Aib, Ac4c, Ac5c, or U;
aa 36 is absent or Ile, Aib, Ac4c, Ac5C, or U;
aa 36 is absent or Ala, Aib, Ac4c, Ac5C, or U;
aa 37 is absent or U;
U is a natural or unnatural amino acid comprising a functional group used for covalent attachment to the surfactant X;
wherein any two of aa 1 -aa 37 are optionally cyclized through their side chains to form a lactam linkage; and
provided that one, or at least one of aa 10 -aa 25 or aa 30 -aa 37 is the linker amino acid U covalently attached to X.
2 . The peptide product of claim 1 , wherein n is 1 or 2.
3 . A peptide product of claim 1 , wherein X has the structure:
wherein:
R 1a is H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, or a steroid nucleus containing moiety;
R 1b , R 1c , and R 1d are each, independently at each occurrence, H, a protecting group, a saccharide, or a substituted or unsubstituted C 1 -C 30 alkyl group;
W 1 is independently, at each occurrence, —CH 2 —, —CH 2 —O—, —(C═O), —(C═O)—O—, —(C═O)—NH—, —(C═S)—, —(C═S)—NH—, or —CH 2 —S—;
W 2 is —O—, —S—;
R 2 is a bond, —NH—, —S—, —NH(C═O)—CH 2 — or —(CH 2 ) m -maleimide-; and
m is an integer of 1-10.
4 . The peptide product of claim 3 , wherein X has the structure:
5 . The peptide product of claim 3 , wherein X has the structure:
6 . The peptide product of claim 3 , wherein X has the structure:
wherein:
R 1a is H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, or a steroid nucleus containing moiety;
R 1b , R 1c , and R 1d are each, independently at each occurrence, H, a protecting group, or a substituted or unsubstituted C1-C30 alkyl group;
W 1 is —(C═O)—NH—;
W 2 is —O—; and
R 2 is a bond.
7 . The peptide product of claim 3 , wherein X has the structure:
wherein:
R 1a is a substituted or unsubstituted C 1 -C 30 alkyl group;
R 1b , R 1c , and R 1d are H;
W 1 is —(C═O)—NH—;
W 2 is —O—; and
R 2 is a bond.
8 . The peptide product of claim 1 , wherein R 1a is a substituted or unsubstituted C 1 -C 30 alkyl group.
9 . The peptide product of claim 1 , wherein R 1a is a substituted or unsubstituted C 6 -C 20 alkyl group.
10 . The peptide product of claim 1 , wherein R 1a is a substituted or unsubstituted C 12 -C 20 alkyl group.
11 . The peptide product of claim 1 , wherein the surfactant X is a 1-alkyl glycoside class surfactant.
12 . The peptide product of claim 1 , wherein X comprises 1-eicosyl beta-D-glucuronic acid, 1-octadecyl beta-D-glucuronic acid, 1-hexadecyl beta-D-glucuronic acid, 1-tetradecyl beta-D-glucuronic acid, 1-dodecyl beta-D-glucuronic acid, 1-decyl beta-D-glucuronic acid, 1-octyl beta-D-glucuronic acid, 1-eicosyl beta-D-diglucuronic acid, 1-octadecyl beta-D-diglucuronic acid, 1-hexadecyl beta-D-diglucuronic acid, 1-tetradecyl beta-D-diglucuronic acid, 1-dodecyl beta-D-diglucuronic acid, 1-decyl beta-D-diglucuronic acid, 1-octyl beta-D-diglucuronic acid, or functionalized 1-eicosyl beta-D-glucose, 1-octadecyl beta-D-glucose, 1-hexadecyl beta-D-glucose, 1-tetradecyl beta-D-glucose, 1-dodecyl beta-D-glucose, 1-decyl beta-D-glucose, 1-octyl beta-D-glucose, 1-eicosyl beta-D-maltoside, 1-octadecyl beta-D-maltoside, 1-hexadecyl beta-D-maltoside, 1-tetradecyl beta-D-maltoside, 1-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, or 1-octyl beta-D-maltoside, 1-eicosyl beta-D-melibioside, 1-octadecyl beta-D-melibioside, 1-hexadecyl beta-D-melibioside, 1-tetradecyl beta-D-melibioside, 1-dodecyl beta-D-melibioside, 1-decyl beta-D-melibioside, or 1-octyl beta-D-melibioside and the corresponding 6 or 6,6′-dicarboxylates.
13 . The peptide product of claim 1 , wherein U is selected from Lys, Cys, Orn, Glu, or an unnatural amino acid comprising a functional group used for covalent attachment to the surfactant X.
14 . The peptide product of claim 1 , having the structure of Formula III-A
(SEQ. ID. NO. 2)
aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -aa 6 -aa 7 -aa 8 -aa 9 -aa 10 -aa 11 -
aa 12 -aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -aa 20 -
aa 21 -aa 22 -aa 23 -aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -aa 29 -Z
Formula III-A
wherein:
Z is OH, or —NH—R 3 ,
wherein R 3 is H, substituted or unsubstituted C 1 -C 12 alkyl, or a PEG chain of less than 10 Da;
aa 1 is His, N—Ac-His, pGlu-His, or N—R 3 -His;
aa 2 is Ser, Ala, Gly, MePro, Aib, Ac4c, or Ac5c;
aa 3 is Gln or Cit;
aa 4 is Gly or D-Ala;
aa 5 is Thr or Ser;
aa 6 is Phe, Trp, 2FPhe, MePhe, 2FMePhe, or Nal2;
aa 7 is Thr or Ser;
aa 8 is Ser or Asp;
aa 9 is Asp or Glu;
aa 10 is Tyr, Leu, Met, Nal2, Bip, Bip2EtMeO, or U(X);
aa 11 is absent or Ser, Asn, Bip, or U(X);
aa 12 is absent or Lys, Glu, Ser, Arg, or U(X);
aa 13 is absent or Tyr, Gln, Cit, or U(X);
aa 14 is absent or Leu, Met, Nle, or U(X);
aa 15 is absent or Asp, Glu, or U(X);
aa 16 is absent or Ser, Gly, Glu, Ala, Aib, Ac5c, Lys, Arg, or U(X);
aa 17 is absent or Arg, hArg, Gln, Glu, Lys, Cit, Aib, Ac4c, Ac5c, or U(X);
aa 18 is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U(X);
aa 19 is absent or Ala, Val, Aib, Ac4c, Ac5c, or U(X);
aa 20 is absent or Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U(X);
aa 2l is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U(X);
aa 22 is absent or Phe, Trp, Nal2, Aib, Ac4c, Ac5c, or U(X);
aa 23 is absent or Val, Ile, Aib, Ac4c, Ac5c, or U(X);
aa 24 is absent or Ala, Gln, Glu, Cit, or U(X);
aa 25 is absent or Trp, Nal2, or U(X);
aa 26 is Leu;
aa 27 is Leu;
aa 28 is Gln;
aa 29 is Thr;
wherein any two of aa 1 -aa 29 are optionally cyclized through their side chains to form a lactam linkage; and
provided that one, or at least one of aa 10 , aa 11 , aa 12 , aa 16 , aa 17 , aa 18 , aa 19 , aa 20 , aa 21 , aa 22 , aa 23 , aa 24 , or aa 25 , is the natural or unnatural amino acid U covalently attached to X.
15 . The peptide product of claim 1 , having the structure of Formula III-B:
(SEQ. ID. NO. 3)
His 1 -aa 2 -aa 3 -Gly 4 -Thr 5 -aa 6 -Thr 7 -Ser 8 -Asp 9 -aa 10 -
aa 11 -aa 12 -aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -
aa 20 -aa 21 -aa 22 -aa 23 -aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -
aa 29 -aa 30 -Z
Formula III-B
wherein:
Z is OH, or —NH—R 3 ,
wherein R 3 is H, substituted or unsubstituted C 1 -C 12 alkyl, or a PEG chain of less than 10 Da;
aa 2 is Gly, MePro or Aib;
aa 3 is Gln or Cit;
aa 6 is Phe, 2FPhe, MePhe, 2FMePhe, or Nal2;
aa 10 is Tyr, Nal2, Bip, Bip2EtMeO, or U(X);
aa 11 is absent or Ser, Asn, Bip, or U(X);
aa 12 is absent or Lys, Glu, Ser, or U(X);
aa 13 is absent or Tyr, Gln, Cit, or U(X);
aa 14 is absent or Leu, Nle, or U(X);
aa 15 is absent or Asp, Glu, or U(X);
aa 16 is absent or Ser, Gly, Glu, Ala, Aib, Lys, Arg, or U(X);
aa 17 is absent or Arg, hArg, Gln, Glu, Lys, Cit, Aib, or U(X);
aa 18 is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U(X);
aa 19 is absent or Ala, Aib, or U(X);
aa 20 is absent or Gln, Lys, Arg, Cit, Glu, Aib, or U(X);
aa 21 is absent or Asp, Glu, Leu, Aib, or U(X);
aa 22 is absent or Phe, or U(X)
aa 23 is absent or Val, Ile, Aib or U(X);
aa 24 is absent or Ala, Gln or U(X);
aa 25 is absent or Trp or U(X);
aa 26 is Leu;
aa 27 is Leu;
aa 28 is Gln;
aa 29 is Thr;
aa 30 is absent or Arg or U(X);
wherein any two of aa 1 -aa 23 are optionally cyclized through their side chains to form a lactam linkage; and
provided that one, or at least one of aa 10 , aa 11 , aa 12 , aa 16 , aa 17 , aa 18 , aa 19 , aa 20 , aa 21 , aa 22 , aa 23 , or aa 24 , is the natural or unnatural amino acid U covalently attached to X.
16 . The peptide product of claim 1 , wherein aa 17 is a lysine residue attached to X.
17 - 33 . (canceled)
34 . A pharmaceutical composition comprising a therapeutically effective amount of a peptide product of claim 1 , or acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
35 . A method of treating a condition associated with insulin resistance comprising administration of a peptide product of claim 1 to an individual in need thereof.
36 - 40 . (canceled)
41 . The method of claim 35 , wherein the administration of said glucagon analog causes weight loss.
42 - 78 . (canceled)
79 . The peptide product of claim 1 , having the structure of Formula III-A
(SEQ. ID. NO. 1110)
aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -aa 6 -aa 7 -aa 8 -aa 9 -aa 10 -aa 11 -
aa 12 -aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -aa 20 -
aa 21 -aa 22 -aa 23 -aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -aa 29 -Z
Formula III-A
wherein:
Z is OH, or —NH—R 3 , wherein R 3 is H, or C 1 -C 12 substituted or unsubstituted alkyl, or a PEG chain of less than 10 Da;
aa 1 is His;
aa 2 is Aib;
aa 3 is Gln;
aa 4 is Gly;
aa 5 is Thr;
aa 6 is Phe;
aa 7 is Thr;
aa 8 is Ser;
aa 9 is Asp;
aa 10 is Tyr, Glu, Lys, or U(X);
aa 11 is Ser;
aa 12 is Lys or Glu;
aa 13 is Tyr;
aa 14 is Leu, Glu, or Lys;
aa 15 is Asp;
aa 16 is Glu or Lys;
aa 17 is Gln, Glu, or U(X);
aa 18 is Ala;
aa 19 is Ala;
aa 20 is Lys, Glu or U(X);
aa 21 is Glu;
aa 22 Phe;
aa 23 is Ile;
aa 24 is Gln, Glu, or U(X);
aa 25 is Trp;
aa 26 is Leu;
aa 27 is Leu;
aa 28 is Gln;
aa 29 is Thr;
wherein aa 16 and aa 20 , or aa 10 and aa 14 , or aa 12 and aa 16 are optionally cyclized through their side chains to form a lactam linkage; and
provided that one, or at least one of aa 10 , aa 17 , aa 20 , or aa 24 is the natural or unnatural amino acid U covalently attached to X.Join the waitlist — get patent alerts
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