US 2026/0295055 A1Published application

Glp-1r/gipr/gcgr triple agonist analogue and use thereof

AssigneeShenzhen Bay Laboratory

InventorsWeijun SHEN, Nan ZHENG, Leiming WANG

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Abstract

Provided is a polypeptide or a derivative thereof or a pharmaceutically acceptable salt thereof. The polypeptide or the derivative thereof comprises a structure as represented by Formula (I): X1X2X3GTX6X7X8DX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25LX27X28X29X30P X32SX34X35PPPX39 (I). The structure represented by Formula (I) comprises two amino acids with —SH on the side chain or two amino acids the side chain containing —NH2, —SH or —NH2 being used for linking a modification group. The polypeptide or the derivative thereof or the pharmaceutically acceptable salt thereof exhibits strong agonistic activity on three receptor targets of GLP-1R, GCGR and GIPR, can effectively control blood sugar and reduce body 10 weight, and can be used for preventing or treating metabolic disorder related diseases and the like.

Claims15

Dependent claims

A polypeptide or a derivative or pharmaceutically acceptable salt thereof, wherein the polypeptide or the derivative thereof comprises a structure represented by Formula (I):

(I)
X1X2X3GTX6X7X8DX10X11X12X13X14X15X16X17X18X19X20
X21X22X23X24X25LX27X28X29X30PX32SX34X35PPPX39,
wherein:
X1 is Y, H, 3-iodo-Y, 4-Pal, or 4-amino-F;
X2 is Aib, s, or Ac4c;
X3 is Q, H, or Dab(Ac);
X6 is F, F(2-F), or αMeF;
X7 is T;
X8 is S, HoS, or αMeS;
X10 is Z2, Y, Z1, L, or 4-Pal;
X11 is S or αMeS;
X12 is K, R, or I;
X13 is Z2, Z1, Y, L, A, αMeL, Q, Aib, or Iva;
X14 is Z2, Z1, L, K(Ac), HOL, Npg, or Tle;
X15 is D, E, or Aad;
X16 is K, E, K(Ac), or αMeK;
X17 is R, Z2, Z1, K(Ac), Q, or I;
X18 is Z2, Z1, A, R, or Y;
X19 is A, Q, Aib, H, or K(Ac);
X20 is Q, Z2, Aib, H, R, a, or Z1;
X21 is Z1, D, A, L, Z2, or Aib;
X22 is F or HOF;
X23 is V or I;
X24 is Z2, Q, Z1, or E;
X25 is Z2, Z1, W, or Y;
X27 is L, K, or I;
X28 is A, D, E, Z1, or Z2;
X29 is G or H;
X30 is G or H;
X32 is Z2, Z1, S, or P;
X34 is G or Aib;
X35 is A, Q, or K;
X39 is S or K,
wherein, in the structure represented by Formula (I), two sites in any of the following groups are each independently selected from amino acid Z1 with a side chain containing —SH, or wherein, in the structure represented by Formula (I), two sites in any of the following groups are each independently selected from amino acid Z2 with a side chain containing —NH2:
1) i and i+3;
2) i and i+4;
3) i and i+7;
or
4) i and i+11, wherein:
i is 10, 14, 17, or 21;
the two amino acids Z1 with the side chain containing —SH are each independently selected from C, c, αMeC, HoC, Hoc, Pen, or N-Me-C;
and
the two amino acids Z2 with the side chain containing —NH2 are each independently selected from K, k, αMeK, HoK, Dap, Dab, Orn, or N-Me-K.

41 more elements

A polypeptide derivative or a pharmaceutically acceptable salt thereof, wherein the polypeptide derivative has one of the structures shown in Table A:

TABLE A
Sites
where
modifi-
cation
Name of
groups
Modifi-
Poly-
are
cation
peptide
Amino acid sequence of polypeptide
attached
group
TG1
Y-Aib-QGTFTSDYSKYCDKRAAQCFVQWLLAGGPSSGAPPPS
14, 21
A1
TG2
Y-Aib-QGTFTSDYSKYCDEKRAKCFVQWLLDHHPSSGQPPPS
14, 21
A1
TG3
Y-Aib-QGTFTSDCSKYCDERAAQDFVQWLLAGGPSSGAPPPS
10, 14
A1
TG4
Y-Aib-QGTFTSDCSKYLDECAAQDFVQWLLAGGPSSGAPPPS
10, 17
A1
TG5
Y-Aib-QGTFTSDCSKYLDERAAQCFVQWLLAGGPSSGAPPPS
10, 21
A1
TG6
H-Aib-HGTFTSDYSIYCEKKYAQCFVQWLLAGGPSSGAPPPS
14, 21
A1
TG7
H-Aib-HGTFTSDYSIYCEKRYAQCFVQWLLAGGPSSGAPPPS
14, 21
A1
TG8
H-Aib-HGTFTSDYSIYCEKRYA-Aib-CFVQWLLEGGPSSGAPPPS
14, 21
A1
TG9
Y-Aib-QGTFTSDYSKYLDKCAAQDFVCWLLAGGPSSGAPPPS
17, 24
A1
TG10
H-Aib-HGTFTSDYSKYLDKCYAQDFVCWLLEGGPSSGAPPPS
17, 24
A1
TG11
Y-Aib-QGTFTSDYSILLDKCAQHAFICYLLEGGPSSGAPPPS
17, 24
A1
TG12
Y-Aib-QGTFTSDYSILLDKCAQ-Aib-AFICYLLEGGPSSGAPPPS
17, 24
A1
TG13
H-Aib-HGTFTSDYSRALEKCAARLFICWLLEGGPSSGAPPPS
17, 24
A1
TG14
H-Aib-HGTFTSDYSKYLE-K(Ac)-KYA-Aib-CFVQWLLCGGPSSGA
21, 28
A1
PPPS
TG15
Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSS
21, 28
A1
GAPPPS
TG16
H-Aib-HGTFTSDLSKL-K(Ac)-EEQRQ-Aib-CFIEWLKCGGPPS-Aib-
21, 28
A1
KPPPK
TG17
H-Aib-QGTFTSDLSKQ-K(Ac)-DEQRAKCFIEWLICGGPSSGAPPPS
21, 28
A1
TG18
H-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSS
21, 28
A1
GAPPPS
TG19
(3-iodo-Y)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLL
21, 28
A1
CGGPSSGAPPPS
TG20
(4-Pal)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCG
21, 28
A1
GPSSGAPPPS
TG21
(4-amino-F)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYL
21, 28
A1
LCGGPSSGAPPPS
TG22
Y-s-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSG
21, 28
A1
APPPS
TG23
Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCG
21, 28
A1
GPSSGAPPPS
TG24
Y-Aib-QGTFT-HoS-DYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCG
21, 28
A1
GPSSGAPPPS
TG25
Y-Aib-QGTFTSDYSI-αMeL-HoL-DK-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A1
PSSGAPPPS
TG26
Y-Aib-QGTFTSDYSI-αMeL-Npg-DK-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A1
PSSGAPPPS
TG27
Y-Aib-QGTFTSDYSI-αMeL-Tle-DK-K(Ac)-AQ-Aib-CFIEYLLCGGP
21, 28
A1
SSGAPPPS
TG28
Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEWLLCGGPS
21, 28
A1
SGAPPPS
TG29
Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-CFIEWLLCGGPSSGAP
21, 28
A1
PPS
TG30
Y-Aib-QGTFTSDYSI-αMeL-LDKQAQ-Aib-CFIEYLLCGGPSSGAPP
21, 28
A1
PS
TG31
Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-a-CFIEYLLCGGPSSG
21, 28
A1
APPPS
TG32
Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQHCFIEYLLCGGPSSGA
21, 28
A1
PPPS
TG33
Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQQCFIEYLLCGGPSSGA
21, 28
A1
PPPS
TG34
Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-A-Aib-QCFIEYLLCGGPSS
21, 28
A1
GAPPPS
TG35
Y-Aib-QGTFTSDYSI-αMeL-LDKRAQ-Aib-CFIEYLLCGGPSSGAPP
21, 28
A1
PS
TG36
Y-Aib-QGTFTSDYSI-αMeL-LEK-K(Ac)-AQ-Aib-CFIEYLLCGGPSS
21, 28
A1
GAPPPS
TG37
Y-Aib-QGTFTSDYSI-αMeL-L-Aad-K-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A1
PSSGAPPPS
TG38
Y-Aib-QGTFTSD-4-Pal-SI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCG
21, 28
A1
GPSSGAPPPS
TG39
Y-Aib-QGTFT-αMeS-DYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCG
21, 28
A1
GPSSGAPPPS
TG40
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLC
21, 28
A1
GGPSSGAPPPS
TG41
Y-Aib-Dab(Ac)-GTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLC
21, 28
A1
GGPSSGAPPPS
TG42
Y-Aib-HGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSS
21, 28
A1
GAPPPS
TG43
Y-Ac4c-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPS
21, 28
A1
SGAPPPS
TG44
Y-Aib-QGTFTSDYSILLDKCAQH-Aib-FIEYLLCGGPSSGAPPPS
17, 28
A1
TG45
Y-Aib-QGTFTSDYSILLDK-HOC-AQH-Aib-FIEYLL-HOC-GGPSSG
17, 28
A1
APPPS
TG46
Y-Aib-QGT-F(2-F)-TSDYSILLDKCAQQAFICYLLAGGPSSGAPPPS
17, 24
A1
TG47
Y-Aib-QGT-F(2-F)-TSDYSILLDKQAQQCFIEYLLCGGPSSGAPPPS
21, 28
A1
TG48
Y-Aib-QGT-F(2-F)-TSDYSI-Aib-LDK-K(Ac)-AQQCFIEYLLCGGPS
21, 28
A1
SGAPPPS
TG49
Y-Aib-QGT-F(2-F)-TSDYSILCDKQAQQCFIEYLLAGGPSSGAPPPS
14, 21
A1
TG50
Y-Aib-QGT-F(2-F)-TSDYSILLD-αMeK-K(Ac)-AQQCFIEYLLCGGP
21, 28
A1
SSGAPPPS
TG51
Y-Aib-QGT-F(2-F)-TSDYSILLD-αMeK-K(Ac)-AQ-Aib-CFIEYLICG
21, 28
A1
GPSSGAPPPS
TG52
Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A1
PSSGAPPPS
TG53
Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A5
PSSGAPPPS
TG54
Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A8
PSSGAPPPS
TG55
Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A11
PSSGAPPPS
TG56
Y-Aib-QGT-F(2-F)-TSDY-αMeS-ILLD-αMeK-K(Ac)-AQQCFIEYLL
21, 28
A1
CGGPSSGAPPPS
TG57
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQQCFIEYLL
21, 28
A1
CGGPSSGAPPPS
TG58
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQQC-HOF-IE
21, 28
A1
YLLCGGPSSGAPPPS
TG59
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSG
17, 20
A1
APPPS
TG60
Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDKCAQCAFIEYLLAGGPSSGAPP
17, 20
A1
PS
TG61
Y-Aib-QGT-F(2-F)-TSDY-αMeS-I-αMeL-LD-αMeK-K(Ac)-AQ-Aib-
21, 28
A1
CFIEYLLCGGPSSGAPPPS
TG62
Y-Aib-QGT-F(2-F)-TSDY-αMeS-I-αMeL-LD-αMeK-CAQCAFIEYLL
17, 20
A1
AGGPSSGAPPPS
TG63
H-Aib-HGT-F(2-F)-TSDYSIYLE-K(Ac)-KYA-Aib-CFVQWLLCGGP
21, 28
A1
SSGAPPPS
TG64
H-Aib-HGT-F(2-F)-TSDYSIQ-K(Ac)-EEIAQ-Aib-CFIEWLLCGGPSS
21, 28
A1
GAPPPS
TG65
H-Aib-HGT-F(2-F)-TSDYSIY-K(Ac)-EERAQ-Aib-CFIEWLLCGGPS
21, 28
A1
SGAPPPS
TG66
H-Aib-HGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGG
21, 28
A1
PSSGAPPPS
TG67
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAHCAFIEYLLAGGPSSG
17, 20
A1
APPPS
TG68
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCA-K(Ac)-CAFIEYLLAGGP
17, 20
A1
SSGAPPPS
TG69
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSG
17, 20
A1
APPPS
TG70
H-Aib-HGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSG
17, 20
A1
APPPS
TG71
Y-s-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAP
17, 20
A1
PPS
TG72
Y-Aib-QGTFTSDYSILLDKQAQQCFIEYLLCGGPSSGAPPPS
21, 28
A1
TG73
Y-Ac4c-QGT-F(2-F)-TSDYSILLDKCAQCAFIEYLLEGGPSSGAPPPS
17, 20
A1
TG74
Y-Ac4c-QGT-F(2-F)-TSDYSILLDK-K(Ac)-AQ-Aib-CFIEYLLCGGP
21, 28
A1
SSGAPPPS
TG75
H-Ac4c-HGT-F(2-F)-TSDYSIQLEEIAQ-Aib-CFIEYLLCGGPSSGAP
21, 28
A1
PPS
TG76
Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-c~FIEYLL-c-GGPSSGAP
21, 28
A1
PPS
TG77
Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-Hoc-FIEYLL-Hoc-GGPS
21, 28
A1
SGAPPPS
TG78
Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-αMeC-FIEYLL-αMeC-G
21, 28
A1
GPSSGAPPPS
TG79
Y-Aib-QGT-F(2-F)-TSDYSIQLDK-K(Ac)-AQ-Aib-CFIEYLLCGGPS
21, 28
A1
SGAPPPS
TG80
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLC
21, 28
A11
GGPSSGAPPPS
TG81
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLC
21, 28
A18
GGPSSGAPPPS
TG82
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLC
21, 28
A20
GGPSSGAPPPS
TG83
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLC
21, 28
A22
GGPSSGAPPPS
TG84
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQ-Aib-KFIEY
21, 28
B1
LLKGGPSSGAPPPS
TG85
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-KFIEYLLK
21, 28
B1
GGPSSGAPPPS
TG86
Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-Orn-FIEYLL-Orn-GGPS
21, 28
B1
SGAPPPS
TG87
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSG
17, 20
B1
APPPS
TG88
Y-Aib-QGT-F(2-F)-TSDYSIQLDKKAQKAFIEYLLAGGPSSGAPPPS
17, 20
B1
TG89
Y-Aib-QGTFTSDYSILLDKKAQKAFIEYLLAGGPSSGAPPPS
17, 20
B1
TG90
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSG
17, 20
B1
APPPS
TG91
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSG
17, 20
B7
APPPS
TG92
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSG
17, 20
B16
APPPS
TG93
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSG
17, 20
B20
APPPS
TG94
Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSG
17, 20
B22
APPPS

460 more elements

Dependencies are inferred from the claim text.

Facts

Application: 19/635,834Filed 1 Apr 2026
Priority: CN 202311295490.87 Oct 2023
Published: 1 Oct 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61K 47/60
Obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes: the organic…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application19/635,834Continuation
US 2026/0295055 A1This patent

From the US filing history. Foreign family members aren’t listed.

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