Los ntawm Cocer Peptides 
13 hnub dhau los
Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.
Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.
Kev rog dhau los dhau los ua qhov teeb meem loj thoob ntiaj teb, cuam tshuam tsis tsuas yog kev noj qab haus huv ntawm lub cev tab sis kuj tseem txuas nrog cov kab mob ntev xws li kab mob plawv thiab ntshav qab zib hom 2. Nrhiav kev nyab xeeb thiab ua tau zoo ntawm kev poob phaus tau yog qhov tseem ceeb ntawm kev tshawb fawb kho mob. Tizepatide yog ib yam tshuaj uas ua rau ob lub receptors, muab txoj hauv kev tshiab rau kev kho mob rog.
Daim duab 1: Cov qauv thiab thawj kauj ruam ntawm kev taw qhia molecular los ntawm GIPR thiab GLP1R hauv GIPR-GLP1R dual agonists RG7697-NNCOO90-2746 thiab LY3298176.
Tizepatide's Dual Receptor Agonist Mechanism
(1) GIP Receptor Agonist Mechanism
Physiological Basis ntawm GIP Receptor
GIP receptor yog ib qho tshwj xeeb cell receptor pom nyob rau hauv ntau yam kabmob, nrog rau cov txiav, cov ntaub so ntswg adipose, siab, thiab cov leeg. Nyob rau saum npoo ntawm pancreatic islet β hlwb, thaum GIP cov tshuaj hormones khi rau cov receptor no, nws ua rau txoj hauv kev taw qhia intracellular, ua rau muaj kev nce qib hauv intracellular cAMP. cAMP tom qab ntawd ua kom cov protein kinase A, uas, dhau los ntawm ntau cov tshuaj tiv thaiv, txhawb kev tso tawm insulin.
Hauv cov ntaub so ntswg adipose, ua kom cov GIP receptor tswj adipocytes metabolism. Nws txhawb nqa cov piam thaj los ntawm adipocytes, nce fatty acid synthesis thiab cia, thiab inhibit lipolysis. Kev tshawb fawb qhia tias cov txheej txheem no tuaj yeem cuam tshuam nrog kev nce ntxiv ntawm cov piam thaj thauj khoom (GLUT4), uas pab txhawb cov piam thaj nkag mus rau hauv adipocytes, muab cov ntaub ntawv raw rau cov roj synthesis.
Cov teebmeem ntawm Tizepatide ntawm GIP Receptor
Tizepatide muaj cov qauv zoo ib yam li GIP cov tshuaj hormones thiab tuaj yeem khi rau thiab qhib GIP receptors. Piv nrog rau endogenous GIP, Tizepatide muaj kev sib txuas ruaj khov rau cov receptors, ua kom muaj txiaj ntsig zoo dua ntawm kev taw qhia txoj hauv kev. Kev tshawb fawb tau pom tias tom qab khi rau cov receptors, nws tuaj yeem ua rau nce qib cAMP, yog li txhawb nqa cov tshuaj insulin ntau dua. Nyob rau hauv cov ntaub so ntswg adipose, nws cov kev cai ntawm lipid metabolism tom qab receptor activation enables ob qho tib si qabzib uptake los ntawm adipocytes thiab sib npaug synthesis thiab khaws cia ntawm fatty acids, tiv thaiv kom txhob muaj roj ntau dhau - qhov tseem ceeb ntawm kev tswj cov lipids metabolism.
Daim duab 2: Kev sib piv cov teebmeem ntawm RG7697/NNCOO90-2746 thiab LY3298176 los ntawm kev sim tshuaj, tshwj tsis yog qhov muaj hnub qub qhia (tsuas pom hauv nas).
(2) GLP-1 Receptor Activation Mechanism
Physiological Basis ntawm GLP-1 Receptors
GLP-1 receptor tseem yog lub cell receptor feem ntau faib rau hauv pancreatic β hlwb, lub plab hnyuv, thiab lub hlwb. Hauv pancreatic β hlwb, GLP-1 khi rau cov receptors thiab ua kom cov kev taw qhia los txhawb kev tso tawm insulin. Tsis zoo li GIP, cov teebmeem ntawm GLP-1 yog tswj hwm los ntawm cov ntshav qabzib: nws txhawb nqa cov tshuaj insulin thaum cov ntshav qabzib siab thiab nws cov teebmeem tsis muaj zog thaum cov ntshav qabzib zoo li qub, ua rau nws muaj kev nyab xeeb dua.
Nyob rau hauv lub plab zom mov, ua kom cov GLP-1 receptor prolongs cov zaub mov khaws cia hauv lub plab, tiv thaiv cov ntshav qabzib sai sai, thiab tseem inhibits gastric acid secretion, tiv thaiv plab hnyuv mucosa. Hauv lub hlwb, nws ua rau thaj tsam tswj kev qab los noj mov, txo kev tshaib kev nqhis thiab nce satiety, yog li ua rau txo qis kev noj zaub mov.
Tizepatide cov teebmeem ntawm GLP-1 receptor
Tizepatide muaj kev sib koom ua ke muaj zog rau GLP-1 receptors, thiab thaum ua haujlwm, nws tsim cov teebmeem zoo ib yam li cov endogenous GLP-1. Raws li kev tswj hwm cov ntshav qabzib, nws txhawb kev tsim cov tshuaj insulin raws li cov ntshav qabzib, yog li tswj cov ntshav qabzib zoo dua. Nyob rau hauv lub plab zom mov, nws cov nyhuv ntawm kev ncua lub plab zom mov yog qhia ntau dua li ntawm qee cov tshuaj. Nyob rau hauv lub hlwb, nws qab los noj mov-suppressing nyhuv yog ntau sustained, zoo pab poob phaus.
(3) Synergistic Effects ntawm Dual Receptor Agonism
Synergistic Effects nyob rau hauv cov ntshav Glucose Regulation
Tizepatide ua rau GIP thiab GLP-1 receptors, ua rau cov ntshav qabzib zoo dua. GIP feem ntau txhawb nqa cov tshuaj insulin secretion thaum ntxov postprandial, txo cov ntshav qabzib peaks; GLP-1 tseem ua haujlwm thoob plaws hauv cov txheej txheem postprandial, tsis tsuas yog txhawb nqa cov tshuaj insulin, tab sis kuj tseem ua rau lub plab zom mov, txo cov zaub mov noj, thiab tswj cov ntshav qabzib kom ruaj khov. Ua kom ob qho tib si receptors ib txhij ua rau muaj txiaj ntsig zoo dua tom qab kev tswj ntshav qabzib. Piv txwv li, hauv kev sim tsiaj txhu mob ntshav qab zib, Tizepatide txo qis cov ntshav qabzib hauv ntshav qab zib ntau dua li GIP lossis GLP-1 cov tshuaj ib leeg, thiab cov ntshav qabzib rov qab los sai dua.
Synergistic Effects ntawm Zog Metabolism
Nyob rau hauv cov nqe lus ntawm lub zog metabolism, GIP receptor agonists txhawb cov piam thaj los ntawm cov rog rog, tab sis nyob rau hauv tus ntawm Tizepatide, rog synthesis tsis sau ntau heev. Lub caij no, GLP-1 receptor agonists suppress qab los noj mov, nce satiety, txo calorie kom tsawg, thiab txhawb kev rog rog thiab siv zog. Qhov kev txiav txim thib ob no sib npaug ntawm kev siv zog thiab kev siv nyiaj. Piv txwv li, hauv kev sim tsiaj rog rog, tom qab siv Tizepatide rau ib lub sij hawm, cov tsiaj lub cev hnyav poob, lub cev rog txo, thiab basal metabolism nrawm.
Daim duab 3: Qhov sib txawv ntawm cov synergistic agonists (chimeras) thiab peptide fusion qauv
Kev siv Tizepatide hauv Kev Kho Mob Obesity
(1) Poob qhov hnyav
Cov ntaub ntawv tshawb fawb Preclinical
Hauv kev sim tsiaj txhu, cov nas rog rog tau tswj hwm Tizepatide pom kev poob phaus zuj zus raws sijhawm, nrog kev txo qis dua piv rau pawg tswj hwm. Kev soj ntsuam ntawm lub cev rog tau qhia tias nws tsis yog tsuas yog txo cov rog xwb tab sis kuj txhim kho cov rog, txo cov rog hauv lub cev. Cov txheej txheem tseem ceeb yog ob npaug: ua ntej, ua kom lub GLP-1 receptor suppresses qab los ntawm inhibiting lub hlwb qhov chaw tshaib plab; thib ob, nws txhawb kev hlawv rog thiab nce kev siv hluav taws xob.
Cov pov thawj kuaj mob
Hauv kev sim tshuaj ntsuam xyuas cov neeg mob rog rog, Tizepatide kuj ua rau pom kev poob phaus zoo. Ntau qhov kev soj ntsuam randomized tau pom tias tom qab ib lub sijhawm ntawm kev kho mob, cov neeg mob lub cev hnyav tau txo qis. Piv txwv li, hauv kev sim 24-lub lim tiam, pab pawg kho mob tau ntsib qhov poob qis ntawm kwv yees li 10%, thaum pab pawg placebo pom qhov hloov pauv me ntsis. Tsis tas li ntawd, cov neeg mob lub duav ncig thiab lub duav ncig kuj tau txo qis, qhia tias nws tsis tsuas yog txhawb kev poob phaus tab sis kuj txhim kho cov rog thiab txo cov kev pheej hmoo ntawm kev rog rog.
(2) Kev Txhim Kho ntawm Metabolic Syndrome-Related Indicators
Txhim kho ntshav Glucose Regulation
Cov neeg mob rog rog feem ntau muaj teeb meem ntshav qab zib, thiab Tizepatide txhim kho kev tswj ntshav qabzib thaum txhawb kev poob phaus. Hauv kev sim tshuaj, cov neeg mob tau ntsib kev txo qis hauv cov ntshav qabzib ceev, cov ntshav qabzib tom qab noj mov, thiab hemoglobin A1c (qhov ntsuas ntshav qabzib ntev ntev) tom qab kho. Qhov no yog vim nws ua los ntawm ob lub receptor mechanisms, txhawb cov insulin secretion thiab txhim kho cov insulin rhiab heev, thaum tseem ua rau lub plab zom mov thiab txo kev nqus sai sai. Piv nrog rau cov tshuaj antidiabetic ib txwm siv, nws tsis tsuas yog txo cov ntshav qabzib tab sis kuj txhawb kev poob phaus, muab cov txiaj ntsig zoo dua rau cov neeg mob rog rog.
Kev txhim kho lipid
Kev rog rog feem ntau nrog dyslipidemia, xws li nce triglycerides thiab qis lipoprotein tsawg (HDL) qib. Tizepatide tuaj yeem tswj cov lipids: tom qab kev tswj hwm, cov neeg mob tau txo qis triglyceride thiab nce qib HDL. Qhov no tuaj yeem cuam tshuam nrog nws cov kev tswj hwm ntawm lipid metabolism, xws li txhawb nqa cov piam thaj los ntawm cov rog rog, txo cov roj fatty acid, thiab txhim kho cov roj oxidation, yog li txhim kho lipid profile thiab txo cov kab mob plawv.
(3) Cov txiaj ntsig zoo rau cov hlab plawv
Kev tswj ntshav siab
Kev rog rog yog ib qho ntawm cov kev pheej hmoo rau kev kub siab. Cov kev tshawb fawb soj ntsuam tau pom tias tom qab kho nrog Tizepatide, cov neeg mob systolic thiab diastolic ntshav siab ob leeg txo. Qhov no yuav cuam tshuam nrog kev poob phaus thiab txhim kho cov metabolism: kev poob phaus txo lub nra ntawm lub plawv, thiab txhim kho cov ntshav qabzib thiab qib lipid pab txhawb kev noj qab haus huv ntawm cov hlab ntsha thiab txo cov hlab ntsha. Tsis tas li ntawd, nws cov teebmeem ntawm txoj hnyuv tuaj yeem cuam tshuam ncaj qha rau kev tswj hwm neuroendocrine, yog li tswj ntshav siab.
Kev tiv thaiv kab mob vascular
Kev mob ntev thiab oxidative kev nyuaj siab yog tshwm sim hauv cov neeg mob rog, uas tuaj yeem ua rau cov hlab ntsha endothelium thiab txhawb atherosclerosis. Tizepatide tiv thaiv vascular endothelium los ntawm kev txhim kho cov metabolism, txo cov kev tso tawm ntawm cov kab mob inflammatory, thiab txo qis oxidative kev nyuaj siab. Cov kev tshawb fawb pom tau hais tias tom qab kev kho mob, cov neeg mob cov cim inflammatory xws li C-reactive protein (CRP) txo qis, thiab vascular endothelial function indicators xws li nitric oxide tso tawm tau nce, qhia txog kev txhim kho vascular noj qab haus huv thiab pab tiv thaiv kab mob plawv.
Xaus
Tizepatide qhia tau hais tias muaj peev xwm tseem ceeb hauv kev kho mob rog los ntawm kev ua haujlwm ib txhij ntawm GIP thiab GLP-1 receptors. Nws tsis tsuas yog txhawb kev poob phaus xwb tab sis kuj tseem txhim kho cov ntsuas metabolic xws li ntshav qabzib thiab qib lipid, thaum muab kev tiv thaiv kab mob plawv. Los ntawm nws cov txheej txheem ntau yam ntawm kev ua, nws muaj kev xaiv kho tshiab rau kev rog thiab lwm yam mob.
Qhov chaw
[1] Boer GA, Hay DL, Tups A. Obesity pharmacotherapy: incretin act in the central nervous system[J]. Trends in Pharmacological Sciences, 2023,44(1):50-63.DOI:10.1016/j.tips.2022.11.001.
[2] Jensen TL, Nden ABO, Karstoft K, et al. Tirzepatid. Dual GLP-1 / GIP receptor agonist, Kev kho mob ntshav qab zib hom 2 thiab rog rog [J]. Drugs of the Future, 2023. DOI: 10.3389/fendo.2022.1004044
[3] Willard FS, Douros JD, Gabe MB, et al. Tirzepatid yog ib qho kev tsis sib haum xeeb thiab tsis ncaj ncees dual GIP thiab GLP-1 receptor agonist [J]. Jci Insight, 2020,5(17).DOI:10.1172/jci.insight.140532.
[4] Bastin M, Andreelli F. Dual GIP-GLP1-Receptor Agonists Hauv Kev Kho Mob Ntshav Qab Zib Hom 2: Kev Ntsuam Xyuas luv luv Ntawm Cov Ntaub Ntawv Tshaj Tawm Thiab Kev Kho Mob Muaj Peev Xwm [J]. Diabetes Metabolic Syndrome thiab Obesity-Targets and Therapy, 2019,12:1973-1985.DOI:10.2147/DMSO.S191438.
Cov khoom muaj rau kev tshawb fawb siv nkaus xwb:
