US2022348611A1PendingUtilityA1
Peptide pharmaceuticals
Est. expiryNov 20, 2032(~6.3 yrs left)· nominal 20-yr term from priority
Inventors:John J. Nestor
C07K 1/1077A61K 38/26A61K 38/07A61K 38/095A61K 38/08A61K 38/29C07K 7/06C09D 101/28A61K 38/00C07K 5/06078
66
PatentIndex Score
0
Cited by
0
References
0
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 biologically active peptide product that binds to GLP-1 receptor (GLP1R) and/or glucagon receptor (GCGR) 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 X is 1-alkyl glycoside
wherein
A is a hydrophobic group which is a substituted or unsubstituted C 8 -C 30 alkyl group; and
B is a hydrophilic saccharide covalently attached to the peptide via a linker amino acid U.
2 . The peptide product of claim 1 , wherein the peptide product is synthesized by reaction of a functionalized surfactant with the peptide.
3 . The peptide product of claim 1 , wherein the 1-alkyl glycoside is an O-linked, S-linked, N-linked or C-linked alkyl glycoside.
4 . The peptide product of claim 1 , wherein B is glucuronic acid.
5 . (canceled)
6 . (canceled)
7 . (canceled)
8 . The peptide product of claim 1 , wherein the hydrophilic group in the surfactant X is attached to the peptide via an amide bond.
9 . The peptide product of claim 1 , wherein the surfactant X comprises 1-eicosyl beta-D-glucuronic acid, 1-octadecyl beta-D-glucuronic acid, 1-hexadecyl beta-D-glucuronic acid, 1-tetradecylbeta 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, 1-eicosyl beta-D-melibiouronic acid, 1-octadecyl beta-D-melibiouronic acid, 1-hexadecyl beta-D-melibiouronic acid, 1-tetradecyl beta-D-melibiouronic acid, 1-dodecyl beta-D-melibiouronic acid, 1-decyl beta-D-melibiouronic acid, 1-octyl beta-D-melibiouronic acid or functionalized 1-ecosyl 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-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, 1-octyl beta-D-maltoside, 1-eicosyl beta-D-melibiose, 1-octadecyl beta-D-melibiose, 1-hexadecyl beta-D-melibiose, 1-tetradecyl beta-D-melibiose, 1-dodecyl beta-D-melibiose, 1-decyl beta-D-melibiose, or 1-octyl beta-D-melibiose.
10 . (canceled)
11 . The peptide product of claim 1 , wherein the peptide product comprises a sequence selected from Formula 3-II:
Formula 3-II
(SEQ. ID. NO. 303)
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
wherein:
Z is OH, or —NH—R 3 , wherein R 3 is H or 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, 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, F2Phe, Me2Phe, 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, or Bip2EtMeO;
aa 11 is Ser, Asn, or U;
aa 12 is 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, Aib, Ac5c, Lys, Arg, or U;
aa 17 is absent or Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, 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 Gln, Ala, Glu, Cit, or U;
aa 25 is absent or Trp, Nal2, or U;
aa 26 is absent or Leu, or U;
aa 27 is absent or Met, Val, Nle, Lys, or U;
aa 28 is absent or Asn, Lys, or U;
aa 29 is absent or Thr, Gly, Aib, Ac4c, Ac5c, or U;
aa 30 is absent or Lys, Aib, Ac4c, Ac5c, 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 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 11 aa 37 is the linker amino acid U covalently attached to the surfactant X.
12 . A peptide product of claim 1 , wherein the peptide product comprises a sequence selected from Formula 3-III-A:
Formula 3-III-A
(SEQ. ID. NO. 304)
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
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, N-Ac-His, pGlu-His, or N—R 3 -His;
aa 2 is Ser, Ala, Gly, 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, F2Phe, Me2Phe, 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, or Bip2EtMeO;
aa 11 is Ser, Asn, or U;
aa 12 is 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, Aib, Ac5c, Lys, Arg, or U(X);
aa 17 is absent or Arg, hArg, Gln, Glu, 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 21 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 Gln, Ala, Glu, Cit, or U(X);
aa 25 is absent or Trp, Nal2, or U(X);
aa 26 is absent or Leu, or U(X);
aa 27 is absent or Met, Val, Nle, Lys, or U(X);
aa 28 is absent or Asn, Lys, or U(X);
aa 29 is absent or Thr, Gly, Aib, Ac4c, Ac5c, or U(X);
wherein any two of aa 1 -aa 26 are optionally cyclized through their side chains to form a lactam linkage; and
provided that one, or at least one of 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 or aa 29 is the linker amino acid U covalently attached to the surfactant X.
13 . The peptide product of claim 1 , wherein the peptide product comprises a sequence selected from has a structure of Formula 3-III-B:
Formula 3-III-B
(SEQ. ID. NO. 305)
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 -Z
wherein:
Z is OH, or —NH—R 3 , wherein R 3 is H or substituted or unsubstituted C 1 -C 12 alkyl; or a PEG chain of less than 10 Da;
aa 2 is Ser, Ala, Gly, Aib, Ac4c, or Ac5c;
aa 3 is Gln, or Cit;
aa 6 is Phe, Trp, F2Phe, Me2Phe, MePhe, or Nal2;
aa 10 is Tyr, Leu, Met, Nal2, Bip, or Bip2EtMeO;
aa 11 is Ser, Asn, or U(X);
aa 12 is Lys, Glu, Ser, 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, Aib, Ac4c, Ac5c, Lys, R, or U(X);
aa 17 is absent or Arg, hArg, Gln, Glu, 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 21 is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U(X);
aa 22 is absent or Phe, Aib, Ac4c, Ac5c, or U(X)
aa 23 is absent or Val, Ile, Aib, Ac4c, Ac5c, 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 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 the surfactant X.
14 . A peptide product of claim 1 , wherein the surfactant X has the structure:
wherein:
A is a substituted or unsubstituted C 1 -C 20 alkyl chain;
R 1b , R 1c , and R 1d are each, independently at each occurrence, H, a protecting group, 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— or —S—;
R 2 is a bond to U, C 2 -C 4 -alkene, C 2 -C 4 -alkyne, or —(CH 2 ) m -maleimide; and
m is 1-10.
15 . The peptide product of claim 1 , wherein the surfactant X has the structure:
16 . The peptide product of claim 1 , wherein the surfactant X has the structure:
17 . The peptide product of claim 1 , wherein the surfactant X has the structure:
wherein:
A is a substituted or unsubstituted C 8 -C 20 alkyl group;
R 1b , R 1c , and R 1d are each, independently at each occurrence, H, a protecting group, or a substituted or unsubstituted C 1 -C 30 alkyl group;
W 1 is —(C═O)—NH—;
W 2 is —O—;
R 2 is a bond to U.
18 . The peptide product of claim 1 , wherein X has the structure:
wherein:
A is a substituted or unsubstituted C 8 -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 to U.
19 . The peptide product of claim 1 , wherein A is a substituted or unsubstituted C 8 -C 20 alkyl group.
20 - 37 . (canceled)
38 . A pharmaceutical composition comprising a therapeutically effective amount of a peptide product of claim 1 , or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
39 . (canceled)
40 . A method of inducing weigh loss comprising administering to a subject in need thereof a therapeutically effective amount of the peptide product of claim 1 .
41 . A method of preparing the peptide product of claim 1 wherein the peptide that binds to GLP-1 receptor (GLP1R) and/or glucagon receptor (GCGR) is synthesized using solid phase synthesis followed by acid-based deprotection and cleavage from a resin and purification by high performance liquid chromatography, wherein the surfactant X of claim 1 is covalently attached to the peptide to form the peptide product.
42 - 47 . (canceled)
48 . A method of treating metabolic syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of the peptide product of claim 1 .
49 . The method of claim 48 , wherein the therapeutically effective amount is from about 0.1 mg/kg/day to about 100.0 mg/kg/day, or from about 0.01 mg/kg/day to about 1 mg/kg/day or from about 0.1 mg/kg/day to about 50 mg/kg/day.Join the waitlist — get patent alerts
Track US2022348611A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.