Retatrutid (GLP-3) 10 mg

▎ GLP-3 Structure

▎ Molecular Background

GLP-3 (LY3437943) yog ib qho kev tshawb nrhiav peptide piav raws li triple receptor agonist ntawm glucagon-zoo li peptide-1 receptor (GLP-1R), qabzib-dependent insulinotropic polypeptide receptor (GIPR), thiab glucagon receptor (GCGR).[1,2]

Fig1. Schematic sawv cev ntawm peb txoj hauv kev receptor tau tham txog GLP-3 hauv qhov kev tshuaj xyuas uas raug txheeb xyuas.[1]

Kev Tshawb Fawb Kev Tshawb Fawb

Coskun, Tamer, thiab cov npoj yaig tau kawm GLP-3 hauv C57 / Bl6 noj zaub mov vim rog rog (DIO) nas. Cov kws sau ntawv tau tshaj tawm cov kev hloov pauv ntawm koob tshuaj hauv lub cev qhov hnyav, calorie kom tsawg, lub cev muaj pes tsawg leeg, ntshav qabzib, insulin, ALT, thiab siab triglycerides. Cov kev sim ntxiv hauv tib txoj kev tshawb fawb tau siv los tshuaj xyuas qhov kev koom tes ntawm GCGR, GIPR, thiab GLP-1R cov cim qhia rau cov lus teb tau pom ua ntej lawm.[2]

Fig 2. Lub cev hnyav, calorie ntau ntau, lub cev muaj pes tsawg leeg, thiab cov ntsiab lus metabolic tau tshaj tawm rau LY3437943 hauv cov nas rog rog rog.

Noj cov nas rog rog tau txais ib zaug ib hnub (QD) nce koob tshuaj ntawm LY3437943 rau 21 hnub hauv txoj kev tshawb fawb.

(A) Hloov qhov feem pua ​​​​ntawm lub cev hnyav dhau sijhawm.

(B) Cov calorie ntau ntau dhau sijhawm.

(C – F) Lub cev muaj pes tsawg leeg hloov hauv grams ntawm qhov kawg ntawm txoj kev tshawb no: lub cev hnyav (C), rog loj (D), lean mass (E), thiab lean / fat mass ratio (F).

(G - J) Cov kab mob metabolic thaum kawg ntawm txoj kev tshawb no: ntshav qabzib (G), insulin (H), ALT (I), thiab lub siab triglycerides (J).

(K) Kev sib piv ntawm LY3437943 nrog GLP-2 ntawm qhov kev tshawb fawb-qhib koob tshuaj rau feem pua ​​​​ntawm kev hloov pauv hauv lub cev hnyav dhau sijhawm.

(L) Kev sib piv ntawm LY3437943 nrog GLP-2 ntawm qhov kev tshawb fawb-qhib koob tshuaj rau calorie ntau ntau dhau sijhawm.

Cov ntaub ntawv qhia tau hais tias txhais tau tias ± SEM nrog n = 6 (A – L). Kev txheeb xyuas kev txheeb xyuas hauv (C) - (K) tau ua tiav siv ib-txoj kev ANOVA piv rau lub tsheb, nrog qhov tseem ceeb ntawm p <0.05. ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 0.0001 vs tsheb, p < 0.05 vs GLP-2. ALT, alanine aminotransferase; LY, LY3437943; SEM, tus qauv yuam kev ntawm qhov nruab nrab.+

Li, Wen Zhou, et al. siv cryo-electron microscopy los tshuaj xyuas GLP-3 khi rau GLP-1R, GIPR, thiab GCGR. Cov kws sau ntawv tau tshaj tawm tias thaj tsam N-terminal ntawm peptide cuam tshuam nrog receptor transmembrane binding hnab tshos, thaum thaj tsam C-terminal txhawb kev cuam tshuam nrog cov cheeb tsam extracellular receptor. Txoj kev tshawb no tau txheeb xyuas ob qho tib si khaws cia thiab cov neeg txais kev sib cuag tshwj xeeb thoob plaws peb lub receptor complexes.[3]

Joachim Neumann thiab cov npoj yaig tau tshuaj xyuas GLP-3 hauv tib neeg txoj cai atrial npaj tau txais thaum phais plawv. Cov kws sau ntawv tau tshaj tawm cov kev hloov pauv- thiab lub sijhawm nyob ntawm qhov kev quab yuam ntawm kev cog lus thiab siv cov receptor antagonists los tshawb xyuas qhov kev koom tes ntawm GCGR, GIPR, thiab GLP-1R. Lawv tau tshaj tawm ib qho kev qhia txog cAMP raws li cov xwm txheej ntawm kev kawm ex vivo no.[4]

Coskun et al. kuj tau tshaj tawm cov kev tshawb fawb txog kev nyab xeeb ntawm lub plawv tsis ua haujlwm hauv cynomolgus liab. Hauv kev tshawb fawb ib zaug ib zaug, lub plawv dhia tau siab dua li kev tswj hwm tam sim tom qab LY3437943 raug, nrog rau qhov kev kawm loj dua uas ua rau muaj kev nce ntxiv. Hauv kev tshawb fawb txog rau-hli rov ua dua koob tshuaj, tau pom lub plawv dhia siab dua thaum lub sijhawm noj tshuaj thiab tau piav qhia raws li kev siv tshuaj ntau dua; Kev hloov pauv hauv systolic thiab diastolic ntshav siab kuj tau tshaj tawm lawm.[2] Cov kev soj ntsuam no tau tsim nyob rau hauv cov kev tshawb fawb tsis yog tib neeg primate.

Kev tshawb fawb txwv

Tsiaj qauv muab cov ntaub ntawv nyob rau hauv cov kev sim uas tau hais tseg tab sis tsis tuaj yeem ua kom tiav qhov nyuaj ntawm tib neeg lub cev. Qhov sib txawv ntawm receptor biology, neuroendocrine adaptation, lub sij hawm raug, thiab downstream signaling yuav cuam tshuam rau kev txhais lus thoob plaws hom. Kev tshawb pom los ntawm kev soj ntsuam receptor, kev tshawb fawb txog cov qauv, cais tib neeg cov ntaub so ntswg, thiab tsiaj cov qauv yuav tsum yog li ntawd yuav tsum tau txhais nyob rau hauv cov qauv siv thiab yuav tsum tsis txhob raug kho raws li pov thawj ntawm kev nyab xeeb kev kho mob los yog kev ua tau zoo.[2,4-6]

COCER Peptides muab GLP-3 tsuas yog siv rau kev tshawb fawb hauv chav kuaj thiab tsis siv rau tib neeg lossis kws kho tsiaj. Cov ntaub ntawv ntawm nplooj ntawv no qhia txog cov kev tshawb pom nyob rau hauv cov ntaub ntawv hais txog lwm tus neeg sab nrauv thiab tsis hais txog kev ua tau zoo, kev nyab xeeb, kev kuaj mob, kev kho mob, kev tiv thaiv, lossis lwm yam kev siv tib neeg.

▎ Cov Lus Qhia Tseem Ceeb

[1] KAUR M, MISRA S. Kev tshuaj xyuas cov tshuaj tshawb xyuas GLP-3, tus neeg sawv cev tshiab triple agonist rau kev kho mob rog rog [J]. European Journal of Clinical Pharmacology, 2024,80(5): 669-676.

PIB: 10.1007/s00228-024-03646-0

[2] COSKUN T, URVA S, ROELL WC, et al. LY3437943, ib qho tshiab triple glucagon, GIP, thiab GLP-1 receptor agonist rau glycemic tswj thiab poob phaus: Los ntawm kev tshawb pom mus rau cov ntaub ntawv pov thawj ntawm lub tswv yim [J]. Cell Diabetes, 2022,34(9):1234-1247.e9.

DOI: 10.1016/j.cmet.2022.07.013

[3] LI W, ZHOU Q, CONG Z, et al. Cov qauv kev pom zoo rau peb lub agonism ntawm GLP-1R, GIPR thiab GCGR tshwm sim los ntawm GLP-3 [J]. Cell Discovery, 2024, 10:77.

PIB: 10.1038/s41421-024-00700-0

[4] NEUMANN J, AHLREP U, HOFMANN B, et al. Inotropic teebmeem ntawm GLP-3 nyob rau hauv cais tib neeg atrial npaj [J]. Naunyn-Schmiedeberg's Archives of Pharmacology, 2026,399(1):317-327.

PIB: 10.1007/s00210-025-04421-3

[5] LUTZ T A. Mammalian qauv ntawm ntshav qab zib mellitus, nrog rau kev tsom mus rau hom 2 mob ntshav qab zib mellitus[J]. Nature Reviews Endocrinology, 2023,19(6:350-360.

PIB: 10.1038/s41574-023-00818-3

[6] TU Q, LIU G, LIU X, et al. Txoj kev xav ntawm kev siv cov primates uas tsis yog tib neeg hauv kev tshawb fawb Exposome [J]. Ecotoxicology thiab Environmental Safety, 2024,286:117199. DOI: 10.1016/j.ecoenv.2024.117199.

Txhua yam khoom, kab lus, cov khoom siv cuab yeej cuab tam, cov lus piav qhia, thiab lwm yam ntaub ntawv muab rau hauv lub vev xaib no yog npaj rau tsuas yog rau kev tshawb fawb raug cai hauv LABORATORY RESEARCH, INFORMATIONAL, THIAB PUBUCATION. 

Cov khoom lag luam muab los ntawm Cocer Peptides yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro thiab kuaj thiab tsis yog siv rau tib neeg lossis kws kho tsiaj, kev siv tib neeg, kev siv tshuaj kho mob, kev siv tshuaj kho mob, kev sib xyaw ua ke, kev tswj hwm tus kheej, kev txhaj tshuaj, lossis lwm yam kev tswj hwm rau tib neeg lossis tsiaj txhu. Cov khoom no tsis yog tsim los kuaj xyuas, kho, kho, txo, lossis tiv thaiv txhua yam kab mob lossis kev kho mob, thiab tsis yog tsim los cuam tshuam rau cov qauv lossis kev ua haujlwm ntawm tib neeg lossis tsiaj lub cev. Tshwj tsis yog hais qhia lwm yam, cov khoom muaj nyob rau hauv lub vev xaib no tsis tau raug soj ntsuam lossis pom zoo los ntawm US Food and Drug Administration (FDA) rau tib neeg lossis kws kho tsiaj. Ib qho kev xa mus rau cov kev tshawb fawb luam tawm, txoj hauv kev biochemical, cov txheej txheem molecular, lossis kev sim tshawb pom tsuas yog muab rau kev sib tham txog kev tshawb fawb thiab kev tshawb fawb thiab tsis yog cov lus qhia kho mob, kev thov kho mob, kev qhia noj tshuaj, lossis cov lus qhia rau kev siv. Cov neeg yuav khoom tsuas yog lub luag haujlwm los xyuas kom meej tias tag nrho cov khoom tau txais, tuav, khaws cia, siv, thiab pov tseg raws li cov kev cai lij choj, cov cai, cov cai hauv tsev, thiab cov qauv kev nyab xeeb.