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(Pro3)-Gastric Inhibitory Polypeptide (human)

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(Pro3)-Gastric Inhibitory Polypeptide (human) is an antagonist of GIP.

Category

Peptide Inhibitors

Catalog number

BAT-014594

CAS number

299898-52-5

Molecular Formula

C226H338N60O64S

Molecular Weight

4951.60

Specification
Reference Reading

IUPAC Name

(2S)-5-amino-2-[[(2S,3R)-2-[[(2S,3S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[[(2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-1-[(2S)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]propanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-carboxypropanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-carboxypropanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-oxobutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]hexanoyl]amino]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-oxobutanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-5-oxopentanoic acid

Synonyms

(Pro3)-GIP (human); H-Tyr-Ala-Pro-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln-OH; L-tyrosyl-L-alanyl-L-prolyl-glycyl-L-threonyl-L-phenylalanyl-L-isoleucyl-L-seryl-L-alpha-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-L-alanyl-L-methionyl-L-alpha-aspartyl-L-lysyl-L-isoleucyl-L-histidyl-L-glutaminyl-L-glutaminyl-L-alpha-aspartyl-L-phenylalanyl-L-valyl-L-asparagyl-L-tryptophyl-L-leucyl-L-leucyl-L-alanyl-L-glutaminyl-L-lysyl-glycyl-L-lysyl-L-lysyl-L-asparagyl-L-alpha-aspartyl-L-tryptophyl-L-lysyl-L-histidyl-L-asparagyl-L-isoleucyl-L-threonyl-L-glutamine

Appearance

White Lyophilized Powder

Purity

≥95%

Sequence

YAPGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ

Storage

Store at -20°C

Solubility

Soluble in Water

InChI

InChI=1S/C226H338N60O64S/c1-21-114(11)181(284-216(339)165(108-288)277-201(324)150(89-126-62-66-132(292)67-63-126)263-210(333)163(100-179(308)309)273-215(338)164(107-287)278-221(344)183(116(13)23-3)282-213(336)152(88-124-48-29-26-30-49-124)274-223(346)185(121(18)289)279-175(301)106-245-217(340)166-59-45-82-286(166)225(348)120(17)250-189(312)135(232)86-125-60-64-131(291)65-61-125)219(342)249-119(16)188(311)253-146(76-83-351-20)197(320)271-160(97-176(302)303)208(331)257-142(58-39-44-81-231)198(321)281-182(115(12)22-2)220(343)275-156(93-130-104-241-110-247-130)204(327)259-144(69-73-168(234)294)195(318)258-145(70-74-169(235)295)196(319)270-161(98-177(304)305)209(332)264-151(87-123-46-27-25-28-47-123)212(335)280-180(113(9)10)218(341)276-158(95-172(238)298)207(330)265-154(91-128-102-243-137-53-34-32-51-134(128)137)203(326)262-149(85-112(7)8)200(323)261-148(84-111(5)6)199(322)248-118(15)187(310)252-143(68-72-167(233)293)194(317)254-138(54-35-40-77-227)190(313)244-105-174(300)251-139(55-36-41-78-228)191(314)255-140(56-37-42-79-229)193(316)268-157(94-171(237)297)206(329)272-162(99-178(306)307)211(334)266-153(90-127-101-242-136-52-33-31-50-133(127)136)202(325)256-141(57-38-43-80-230)192(315)267-155(92-129-103-240-109-246-129)205(328)269-159(96-173(239)299)214(337)283-184(117(14)24-4)222(345)285-186(122(19)290)224(347)260-147(226(349)350)71-75-170(236)296/h25-34,46-53,60-67,101-104,109-122,135,138-166,180-186,242-243,287-292H,21-24,35-45,54-59,68-100,105-108,227-232H2,1-20H3,(H2,233,293)(H2,234,294)(H2,235,295)(H2,236,296)(H2,237,297)(H2,238,298)(H2,239,299)(H,240,246)(H,241,247)(H,244,313)(H,245,340)(H,248,322)(H,249,342)(H,250,312)(H,251,300)(H,252,310)(H,253,311)(H,254,317)(H,255,314)(H,256,325)(H,257,331)(H,258,318)(H,259,327)(H,260,347)(H,261,323)(H,262,326)(H,263,333)(H,264,332)(H,265,330)(H,266,334)(H,267,315)(H,268,316)(H,269,328)(H,270,319)(H,271,320)(H,272,329)(H,273,338)(H,274,346)(H,275,343)(H,276,341)(H,277,324)(H,278,344)(H,279,301)(H,280,335)(H,281,321)(H,282,336)(H,283,337)(H,284,339)(H,285,345)(H,302,303)(H,304,305)(H,306,307)(H,308,309)(H,349,350)/t114-,115-,116-,117-,118-,119-,120-,121+,122+,135-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,180-,181-,182-,183-,184-,185-,186-/m0/s1

InChI Key

FYUWJDFZJSKUGR-STMGAEMMSA-N

Canonical SMILES

CCC(C)C(C(=O)NC(CC1=CN=CN1)C(=O)NC(CCC(=O)N)C(=O)NC(CCC(=O)N)C(=O)NC(CC(=O)O)C(=O)NC(CC2=CC=CC=C2)C(=O)NC(C(C)C)C(=O)NC(CC(=O)N)C(=O)NC(CC3=CNC4=CC=CC=C43)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C)C(=O)NC(CCC(=O)N)C(=O)NC(CCCCN)C(=O)NCC(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CC(=O)N)C(=O)NC(CC(=O)O)C(=O)NC(CC5=CNC6=CC=CC=C65)C(=O)NC(CCCCN)C(=O)NC(CC7=CN=CN7)C(=O)NC(CC(=O)N)C(=O)NC(C(C)CC)C(=O)NC(C(C)O)C(=O)NC(CCC(=O)N)C(=O)O)NC(=O)C(CCCCN)NC(=O)C(CC(=O)O)NC(=O)C(CCSC)NC(=O)C(C)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(CC8=CC=C(C=C8)O)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)CC)NC(=O)C(CC9=CC=CC=C9)NC(=O)C(C(C)O)NC(=O)CNC(=O)C1CCCN1C(=O)C(C)NC(=O)C(CC1=CC=C(C=C1)O)N

1. Species-specific action of (Pro3)GIP - a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors

A H Sparre-Ulrich, L S Hansen, B Svendsen, M Christensen, F K Knop, B Hartmann, J J Holst, M M Rosenkilde Br J Pharmacol. 2016 Jan;173(1):27-38. doi: 10.1111/bph.13323. Epub 2015 Nov 20.

Background and purpose: Specific, high potency receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose-dependent, insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist, (Pro3)GIP, and its effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system. Experimental approach: Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition binding using (125) I-human GIP. Using isolated perfused pancreata both from wild type and GIP receptor-deficient rodents, insulin-releasing, glucagon-releasing and somatostatin-releasing properties in response to species-specific GIP and (Pro3)GIP analogues were evaluated. Key results: Human (Pro3)GIP is a full agonist at human GIP receptors with similar efficacy (Emax ) for cAMP production as human GIP, while both rat and mouse(Pro3)GIP were partial agonists on their corresponding receptors. Rodent GIPs are more potent and efficacious at their receptors than human GIP. In perfused pancreata in the presence of 7 mM glucose, both rodent (Pro3)GIP analogues induced modest insulin, glucagon and somatostatin secretion, corresponding to the partial agonist activities observed in cAMP production. Conclusions and implications: When evaluating new compounds, it is important to consider interspecies differences both at the receptor and ligand level. Thus, in rodent models, human GIP is a comparatively weak partial agonist. Human (Pro3)GIP was not an antagonist at human GIP receptors, so there is still a need for a potent antagonist in order to elucidate the physiology of human GIP.

2. Effects of the novel (Pro3)GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

V A Gault, F P M O'Harte, P Harriott, M H Mooney, B D Green, P R Flatt Diabetologia. 2003 Feb;46(2):222-30. doi: 10.1007/s00125-002-1028-x. Epub 2003 Feb 12.

Aims/hypothesis: This study examined the biological effects of the GIP receptor antagonist, (Pro3)GIP and the GLP-1 receptor antagonist, exendin(9-39)amide. Methods: Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic ( ob/ ob) mice. Results: In GIP receptor-transfected fibroblasts, (Pro(3))GIP or exendin(9-39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0+/-3.5% and 73.5+/-3.2% at 10(-6) mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin(9-39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60+/-0.7% at 10(-6) mol/l, whereas (Pro(3))GIP had no effect. (Pro(3))GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9-39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro(3))GIP, exendin(9-39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro3)GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small. Conclusions/interpretation: These data show that (Pro(3))GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release.

3. Dorothy Hodgkin Lecture 2008. Gastric inhibitory polypeptide (GIP) revisited: a new therapeutic target for obesity-diabetes?

P R Flatt Diabet Med. 2008 Jul;25(7):759-64. doi: 10.1111/j.1464-5491.2008.02455.x.

There is increasing realization that gastric inhibitory polypeptide (GIP) has actions outside of the pancreas and gastrointestinal tract. Most significant is the presence of functional GIP receptors on adipocytes and the appreciation that GIP, secreted strongly in response to fat ingestion, plays a role in the translation of excessive amounts of dietary fat into adipocyte tissue stores. Such effects open up the possibility of exploiting GIP receptor antagonism for the treatment of obesity and insulin resistance. This is borne out by studies in high-fat-fed mice or ob/ob mice with either genetic knockout of GIP receptor or chemical ablation of GIP action using the GIP receptor antagonist, (Pro3)GIP. By causing preferential oxidation of fat, blockade of GIP signalling clears triglyceride deposits from liver and muscle, thereby respectively restoring mechanisms for suppression of hepatic glucose output and cellular glucose uptake. Further studies are needed to determine the applicability of this research to human obesity-diabetes. However, proof of concept is provided by emerging evidence that rapid cure of diabetes in grossly obese subjects undergoing Roux-en-Y bypass surgery is mediated in part by surgical bypass of GIP-secreting K-cells in the upper small intestine.