Shaanxi BLOOM Tech Co., Ltd. yog ib qho ntawm feem kev paub manufacturers thiab lwm tus neeg ntawm survodutide peptide nyob rau hauv Suav teb. Txais tos rau cov lag luam wholesale bulk zoo survodutide peptide muag ntawm no los ntawm peb lub hoobkas. Kev pabcuam zoo thiab tus nqi tsim nyog muaj.
Survodutide peptide, ib qho tshiab dual GLP-1/glucagon receptor agonist, harbors ib tug tsawg dua - tham txog complexity nyob rau hauv nws structural dynamics uas nyuaj rau cov pa peptide tshuaj paradigms. Tsis zoo li GLP ib txwm siv-1 analogs, nws cov qauv tsim qauv zoo nkauj- sib koom ua ke glucagon's helical domain nrog GLP-1's C-terminal tail- tsim cov metastable conformation prone rau pH-dependent aggregation, feem ntau muaj ntau yam ntxoov ntxoo. los ntawm nws cov txiaj ntsig metabolic. Qhov kev tsis ruaj khov no yuav tsum muaj cov txheej txheem txawv txav xws li tsis yog-aqueous co- cov kuab tshuaj (xws li, DMSO cov kab hauv cov hmoov lyophilized) los tiv thaiv kev tsim fibril thaum lub sij hawm cia, ib qho kev tawm tswv yim qiv los ntawm kev tshawb fawb kab mob neurodegenerative. Curiously, nws cov glucagon moiety qhov cuam tshuam rau proteolytic clipping los ntawm dipeptidyl peptidase-4 (DPP-4)-txawm tias tsis muaj cov canonical cleavage site-reveals cryptic enzyme recognition motifs los ntawm molecular dynamics simulations ntawm kev tawm tswv yim. Lub peptide's unorthodox disulfide choj network, suav nrog ib lub nplhaib 11-tus tswv cuab hauv glucagon ntu, ua rau tsis tshua muaj kev sib xyaw ua ke: spontaneous -elimination thaum lub sij hawm solid-thesis synthesis mandates low-temperature coupling with pseudoproline dipeptides.
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Survodutide hmoov COA
Lub discovery ntawmSurvodutidepeptide(BI 456906) pib los ntawm - tshawb nrhiav qhov tob ntawm cov tswv yim kho mob rau cov kab mob metabolic, tshwj xeeb tshaj yog rau cov kab mob nyuaj xws li rog rog thiab metabolic dysfunction-txog fatty siab kab mob (MASH). Nws cov keeb kwm kev loj hlob tuaj yeem taug qab rov qab mus rau hauv - kev tshawb fawb tob txog kev ua haujlwm ntawm lub cev ntawm glucagon thiab glucagon-zoo li peptide-1 (GLP-1), nrog rau kev sib koom ua ke ntawm lawv cov kev sib cuam tshuam hauv lub zog metabolism.
Kev tshawb fawb thaum ntxov: Lub peev xwm ntawm dual receptor agonists
Glucagon thiab GLP-1 yog cov tshuaj hormones tseem ceeb uas tswj hwm lub zog sib npaug thiab cov ntshav qab zib homeostasis. Glucagon txhawb kev siv hluav taws xob los ntawm kev ua kom cov glucagon receptor (GCGR), thaum GLP-1 inhibits qab los noj mov thiab txhim kho insulin rhiab heev los ntawm activating GLP-1 receptor (GLP-1R). Txawm li cas los xij, ib leeg receptor agonists muaj kev txwv hauv kev kho cov kab mob metabolic. Piv txwv li, GLP-1R agonists (xws li liraglutide, semaglutide) tuaj yeem txo qhov hnyav thiab txhim kho cov ntshav qab zib, tab sis lawv cov kev txhawb zog ntawm kev siv nyiaj tsawg; thaum GCGR agonists tuaj yeem nce kev siv hluav taws xob, lawv tuaj yeem ua rau cov ntshav qab zib nce ntxiv. Yog li, dual receptor agonists uas ib txhij qhib ob qho tib si GCGR thiab GLP-1R raug suav hais tias muaj peev xwm muab cov txiaj ntsig zoo hauv metabolic ntau dua.
Kev tshawb fawb kev tshoov siab rau kev txhim kho ntawm Survodutide yog ib feem los ntawm kev tshawb fawb ntawm cov tshuaj hormone oxyntomodulin (OXM). OXM yog ib qho tsis muaj zog dual receptor agonist uas tuaj yeem ua rau tib lub sijhawm GCCR thiab GLP-1R, thiab tau pom qhov poob phaus thiab kev txhim kho metabolic hauv cov tsiaj sim. Txawm li cas los xij, receptor affinity ntawm OXM yog tsawg thiab nws ib nrab-lub neej yog luv, uas txwv nws daim ntawv thov kev kho mob. Raws li qhov no, cov kws tshawb fawb tau pib tsim thiab tsim kom muaj txiaj ntsig zoo thiab ruaj khov dual receptor agonists. Survodutide yog ib qho kev ua tiav hauv daim teb no.
Molecular Design and Optimization: Ntsuas Kev Ua Haujlwm thiab Kev Nyab Xeeb
Kev tsim qauv molecular ntawm Survodutide lub hom phiaj kom kov yeej cov kev cov nyom ntawm cov tshuaj ib txwm muaj dual receptor agonists, uas yog, ntsuas qhov ua kom sib piv ntawm GCGR thiab GLP-1R kom tsis txhob muaj cov ntshav qab zib hloov pauv. Los ntawm kev ua kom zoo ntawm cov qauv, Survodutide yog tsim los ua ib qho glucagon analogue es tsis yog OXM analogue, nrog rau qhov ua kom piv ntawm GCGR rau GLP-1R yog kwv yees li 1: 8 (cov ntaub ntawv los ntawm kev sim hauv vitro). Qhov qauv piv txwv no ua kom ntseeg tau tias cov teebmeem hypoglycemic thiab yuag poob los ntawm GLP-1R tswj hwm, thaum lub sijhawm ua haujlwm ntawm GCGR nruab nrab nce kev siv hluav taws xob, yog li tswj cov ntshav qab zib kom ruaj khov thaum ua tiav qhov hnyav.
Tsis tas li ntawd, cov qauv molecular ntawm Survodutide suav nrog C18 dicarboxylic pawg, uas tuaj yeem khi rau albumin thiab txuas ntxiv nws ib nrab - lub neej, ua kom cov tshuaj tau siv los ntawm kev txhaj tshuaj subcutaneous ib zaug hauv ib lub lis piam. Qhov kev txhim kho no ua rau muaj txiaj ntsig zoo rau cov neeg mob ua raws li kev kho mob thiab muab kev yooj yim rau kev kho mob ntev -.
Kev tshawb fawb Preclinical: Kev lees paub ntawm kev ua tau zoo thiab kev nyab xeeb
Hauv kev tshawb fawb preclinical, Survodutide tau qhia txog kev txhim kho metabolic tseem ceeb. Cov kev sim tsiaj tau pom tias Survodutide tuaj yeem txo cov zaub mov noj, ua kom lub zog noj, thiab txo lub cev hnyav thiab txhim kho ntshav qab zib. Tsis tas li ntawd, Survodutide kuj tau nthuav tawm cov kev tiv thaiv ncaj qha rau daim siab, muaj peev xwm txo tau daim siab rog deposition thiab txhim kho daim siab fibrosis, uas muab ib tug scientific hauv paus rau nws daim ntawv thov nyob rau hauv MASH kev kho mob.
Kev sim tshuaj kho mob: Ib qho kev tawg ntawm lub tswv yim mus rau qhov tseeb
Kev kho mob ntawm Survodutide tau pib thaum ntxov 2020s thiab sai sai mus rau theem II-theem sim. Nws thawj zaug II- theem sim tau ua rau cov neeg laus rog rog lossis rog tsis muaj ntshav qab zib. Cov txiaj ntsig tau pom tias tom qab 46 lub lis piam ntawm kev kho mob, cov neeg mob hauv 4.8 mg koob tshuaj ntawm Survodutide tau txo qhov hnyav nruab nrab ntawm 18.7% los ntawm lub hauv paus, thiab qhov hnyav poob yog koob tshuaj - nyob ntawm. Tsis tas li ntawd, Survodutide kuj tseem txhim kho cov txiaj ntsig metabolic ntawm cov neeg mob, xws li lub duav ncig, yoo ntshav qabzib (FPG), thiab glycosylated hemoglobin (HbA1c).
Hauv kev kho MASH, cov txiaj ntsig ntawm II theem sim ntawm Survodutide yog qhov zoo sib xws. Tom qab 48 lub lis piam ntawm kev kho mob, nce mus txog 64.5% ntawm cov neeg mob uas muaj F2 thiab F3 theem fibrosis tau paub txog kev txhim kho hauv daim siab fibrosis thiab tsis muaj kev puas tsuaj ntawm MASH, thaum pawg placebo tsuas muaj kev txhim kho 25.9%. Tsis tas li ntawd, Survodutide txo qis cov roj siab hauv lub siab thiab qhov tsis yog - cawv fatty siab kab mob cov qhab nia (NAS) ntawm cov neeg mob, ntxiv txheeb xyuas nws cov peev xwm hauv MASH kev kho mob.
Kev Tswj Xyuas Kev Pom Zoo thiab Kev Pom Zoo yav tom ntej
Raws li nws cov txheej txheem tshiab thiab kev ua tau zoo tshaj plaws, Survodutide tau txais kev xaiv nrawm los ntawm US Food and Drug Administration (FDA) thiab Cov Tshuaj Tseem Ceeb (PRIME) kev txhawb nqa los ntawm European Medicines Agency (EMA). Tam sim no, Survodutide tab tom ntsib ntau qhov kev sim tshuaj Phase III txhawm rau ntsuas nws qhov ntev -kev ua tau zoo thiab kev nyab xeeb hauv kev rog, MASH, thiab lwm yam kab mob metabolic.
Kev xaiv cov kab mob microbial qhia
Survodutidepeptideyog ib tug dual agonist rau glucagon receptor (GCGR) thiab glucagon -zoo li peptide-1 receptor (GLP-1R). Nyob rau hauv tus txheej txheem ntawm nws txoj kev loj hlob, kev xaiv ntawm microbial qhia systems yuav tsum tau ua tib zoo xav txog ntau yam xws li scientific compatibility, kev khwv nyiaj txiag, thiab kev pheej hmoo. Cov kev soj ntsuam hauv qab no yog ua los ntawm peb yam: cov ntsiab lus thev naus laus zis, kev sib piv cov txheej txheem, thiab cov ntaub ntawv siv tswv yim.
Technical Principple: Tom qab-Kev Hloov Kho Kev Hloov Kho Kev Txiav Txim Siab Xaiv Qhov System
Lub molecular tsim ntawmSurvodutidepeptideintegrates cov txheej txheem tseem ceeb ntawm glucagon analogues nrog GLP-1 receptor agonistic muaj nuj nqi, thiab ua tiav kev khi rau albumin los ntawm C18 dicarboxyl pab pawg hloov kho, yog li txuas ntxiv ib nrab - lub neej mus rau kev tswj hwm ib lub lis piam. Qhov kev tsim no imposes ob lub ntsiab lus tseem ceeb ntawm kev qhia qhov system:
Glycosylation muaj peev xwm hloov kho:Txawm hais tias Survodutide nws tus kheej tsis cia siab rau txoj kev glycosylation, post- kev hloov pauv hloov pauv xws li disulfide daim ntawv cog lus tsim thiab amidation uas yuav muaj nyob hauv nws cov molecule yuav tsum tau endoplasmic reticulum-Golgi lub cev ua txoj hauv kev ntawm eukaryotic system. Piv txwv li, cov kab mob mammalian (xws li CHO thiab HEK293) tuaj yeem ua kom muaj kev sib raug zoo ntawm disulfide bonds thiab zam cov teeb meem hauv lub cev uas tshwm sim yooj yim hauv cov kab mob prokaryotic.
Secretion expression efficiency:Survodutide yuav tsum tau ua kom tiav qhov kev ua kom muaj kev sib haum xeeb los ntawm txoj kev zais cia. Txawm hais tias cov kab mob poov xab (xws li Pichia pastoris) muaj peev xwm zais cia, nws cov glycosylation ntau dhau yuav cuam tshuam rau kev nyab xeeb tshuaj; thaum tus qauv glycosylation ntawm kab kab (xws li Sf9) yog ze rau tib neeg, tab sis tus nqi siab dua.
Kev sib piv qhov system: Ntsuas tus nqi, tawm los thiab kev tswj hwm kev pheej hmoo
Prokaryotic system (Escherichia coli)
Qhov zoo: Tus nqi cog qoob loo tsawg, lub voj voog luv luv, tsim nyog rau kev ua haujlwm thaum ntxov. Piv txwv li, 35-amino acid core sequence ntawm Survodutide tuaj yeem nthuav tawm sai sai hauv Escherichia coli rau kev tshawb fawb txog kab mob biology lossis kev npaj antigen.
Kev txwv: Tsis tuaj yeem ua kom tiav cov ntawv tshaj tawm - kev hloov pauv kev txhais lus tshwj xeeb rau eukaryotes, ua rau txo qis kev ua haujlwm; suav nrog lub cev xav tau kev kho dua tshiab, ua kom cov txheej txheem nyuaj. Boehringer Ingelheim tuaj yeem siv cov kab ke no los soj ntsuam cov neeg sib tw cov molecules sai sai nyob rau theem preclinical, tab sis nws tsis yog siv rau kev tsim tshuaj zaum kawg.
Poov xab system (Pichia pastoris)
Qhov zoo: Muab qhov yooj yim ntawm kev ua haujlwm prokaryotic nrog kev hloov kho muaj peev xwm ntawm eukaryotes, haum rau nruab nrab - nplai ntau lawm. Cov methanol-inducible txhawb nqa ntawm Pichia pastoris tuaj yeem ua tiav siab - ntom fermentation, nrog rau cov txiaj ntsig txog li kilogram ib liter.
Kev txwv: Ntau dhau glycosylation tuaj yeem ua rau muaj kev tiv thaiv kab mob, yuav tsum tau kho cov noob (xws li khob tawm cov noob glycosyltransferase) rau kev ua kom zoo. Yog tias Survodutide xaiv cov kab ke no, nws yuav tsum txheeb xyuas qhov cuam tshuam ntawm tus qauv glycosylation ntawm kev siv tshuaj.
Mammalian system (CHO)
Qhov zoo: Kev tswj hwm kev lees paub siab, suav txog 80% ntawm kev ua lag luam sib koom ntawm biopharmaceutical ntau lawm. CHO hlwb tuaj yeem ua kom ruaj khov qhia tag nrho - qhov ntev ntawm Survodutide, kom ntseeg tau qhov sib xws ntawm kev tshaj tawm - hloov pauv kev hloov pauv nrog lub ntuj molecule. Piv txwv li, los ntawm GS gene editing thev naus laus zis, CHO-K1 kab xov tooj ntawm tes tuaj yeem ua rau cov txiaj ntsig tau nce mus rau 8g / L thiab ua kom lub voj voog luv luv uas siv cov thev naus laus zis perfusion.
Kev txwv: Kev tshawb fawb thiab kev tsim kho tus nqi siab, xav tau kev nqis peev hauv kev txhim kho cov kab ke ruaj khov thiab cov khoom siv kab lis kev cai perfusion. Boehringer Ingelheim muaj feem ntau yuav xaiv cov kab ke no hauv III qhov kev sim tshuaj thiab kev lag luam theem kom ntseeg tau tias cov txheej txheem ruaj khov.
Daim Ntawv Thov Kev Pom Zoo: Cov Txheej Txheem Evolution los ntawm Kev Tshawb Fawb Txog Kev Lag Luam
Kev tshawb fawb thaum ntxov:Boehringer Ingelheim tuaj yeem siv HEK293 kev hloov pauv hloov pauv hloov pauv sai sai los tshawb xyuas cov haujlwm ntawm Survodutide. Cov kab ke no tuaj yeem tau txais milligram- qib protein nyob rau hauv ob peb lub lis piam, ua tau raws li qhov yuav tsum tau muaj ntawm kev tshawb fawb pharmacodynamics, thaum zam lub sijhawm ntev - kev nqis peev hauv kev txhim kho cov kab cell ruaj khov.
Kev kho mob ua ntej- theem kev txhim kho:Txhawm rau sib npaug nrawm thiab ua tau zoo, cov kab hluav taws xob ruaj khov lossis CHO cov kab hluav taws xob ruaj khov ua cov kev daws teeb meem. Piv txwv li, qhia Survodutide los ntawm methanol-inducible Pichia pastoris tuaj yeem ua tiav cov khoom toxicology batch hauv 2 lub lis piam; thaum CHO cell kab, txawm hais tias yuav tsum tau 3-6 lub hlis ntawm txoj kev loj hlob, tuaj yeem ua kom cov txheej txheem sib xws.
Clinical thiab lag luam theem:CHO qhov system ua qhov kev xaiv tseem ceeb. Nws qhov zoo nyob hauv:
Kev ua raws cai: FDA / EMA muaj cov lus qhia paub tab rau CHO platform, txo cov kev pheej hmoo pom zoo.
Scale- nce peev xwm: Ua ke nrog kev siv thev naus laus zis thev naus laus zis, ib pawg tawm los tuaj yeem ncav cuag qib kilogram, ua tau raws li kev lag luam thoob ntiaj teb.
Cov cuab yeej cuab tam kev txawj ntse: Boehringer Ingelheim tuaj yeem zam qhov kev tsis sib haum xeeb ntawm patent los ntawm kev xaiv qhib - qhov chaw CHO qhov txawv (xws li GS-KO CHO), thaum siv cov kab lis kev cai hauv tsev los txo cov kev pheej hmoo ntawm cov saw hlau.
Yav Tom Ntej Trends: System Innovation Tsav los ntawm Synthetic Biology
Nrog rau txoj kev loj hlob ntawm hluavtaws biology, cov txheej txheem qhia tshiab tau tawg los ntawm cov kev txwv ib txwm muaj:
Human cell kab (PER.C6)
Yuav txo tau cov tshuaj tiv thaiv kab mob, tab sis yuav tsum muaj kev txheeb xyuas ntxiv ntawm tus kab mob kev nyab xeeb.
Cell -kev qhia pub dawb
Haum rau kev tsim cov proteins uas muaj tshuaj lom sai sai (xws li tshuaj tiv thaiv- mob qog noj ntshav), tab sis tus nqi thiab kev ua kom muaj peev xwm tseem nyob twj ywm.
Kev siv tshuab tsis tu ncua
CHO cell perfusion txheej txheem tuaj yeem ua kom muaj peev xwm ntau lawm los ntawm 3-5 zaug, dhau los ua cov lus qhia tseem ceeb rau kev lag luam yav tom ntej.
Xaus
nws microbial qhia system rauSurvodutide peptidenthuav tawm "theem- tshwj xeeb" yam ntxwv: nyob rau theem pib, kev siv tau sai sai ntawm kev ua haujlwm tau ua tiav los ntawm kev hloov pauv hloov pauv hauv HEK293 hlwb. Thaum lub sij hawm kev txhim kho preclinical, tus nqi -kev ua tau zoo ntawm Pichia pastoris thiab CHO systems yog hnyav. Thaum kawg, nyob rau theem kev lag luam, ib qho chaw ruaj khov CHO cell kab raug xaiv kom sib npaug cov txiaj ntsig, zoo, thiab ua raws. Lub tswv yim no embodies cov ntsiab lus tseem ceeb ntawm "kev hloov pauv kev tshawb fawb tseem ceeb, kev tsav tsheb nyiaj txiag, thiab kev tswj hwm kev pheej hmoo" hauv kev lag luam biopharmaceuticals, muab cov lus qhia txog kev siv rau kev txhim kho ntawm cov receptor agonists zoo sib xws.
Cim npe nrov: survodutide peptide, lwm tus neeg, manufacturers, hoobkas, lag luam wholesale, yuav, nqe, tej, kev muag khoom