G-441524yog ib qho me me molecule, hu ua nucleoside triphosphate kev sib tw inhibitor, uas qhia tau hais tias muaj zog tiv thaiv kab mob tiv thaiv ntau tus kab mob RNA. Nws tuaj yeem tiv thaiv kev rov ua dua ntawm ntau hom kab mob RNA, xws li mob hnyav ua pa nyuaj (SARS) tus mob coronavirus, Middle East respiratory syndrome virus, Ebola virus, Lassa fever virus, Junin virus, thiab tus kab mob ua pa syncytial, thiab muaj cytotoxicity tsawg hauv muaj ntau hom kab ntawm tes.
Action mechanism ntawm gs-441524
Gs-441524 yog phosphorylated rau hauv nucleoside monophosphate (NMP) los ntawm cell kinase hauv cov hlwb thiab tom qab ntawd hloov mus ua ib qho active triphosphate metabolite (NTP structural analog). Hauv cov kab mob RNA synthesis, active NTP structural analogs ua raws li kev sib tw ntawm ntuj nucleosides triphosphate thiab sib tw nrog ntuj nucleosides (ATP, TTP, CTP, GTP) los koom rau hauv RNA transcription. Thaum gs-441524 molecule tau muab tso rau hauv cov ntawv sau tseg, cov ntawv sau yuav raug txiav ua ntej, yog li inhibiting cov txheej txheem hloov pauv ntawm tus kab mob RNA.
Bisulfite adduct gc376yog ib qho dav -spectrum inhibitor, lub npe tshawb fawb 3C protease inhibitor, uas tsom rau 3C protease encoded los ntawm tus kab mob.
Ua haujlwm mechanism ntawm gc376
Raws li lub luag haujlwm tseem ceeb ntawm 3C protease hauv cov kab mob sib kis. Kev thaiv cov cleavage ntawm tus kab mob protease yog qhov tseem ceeb nkag mus rau kev kho tus mob coronavirus.
Gc376 lub hom phiaj 3C protease thiab khi rau qhov chaw nquag ntawm 3C protease. Thaum lub sij hawm cov tshuaj tiv thaiv, gc376 poob cov sulfite pawg qauv thiab nthuav tawm cov aldehyde pawg. Cov pab pawg aldehyde reacted nrog cov nucleophilic cysteine residue (- Cys) ntawm 3clpro los tsim ib daim ntawv cog lus rov qab. Nws cuam tshuam cov catalysis ntawm 3CL zoo li protease thiab tom qab ntawd inhibits qhov rov ua dua ntawm tus kab mob.
Cov kab mob sib kis li cas?
Tom qab cov khoom siv caj ces (RNA, DNA) ntawm tus kab mob extracellular nkag mus rau hauv lub cell (piv txwv li ib txwm cell ntawm ib yam kab mob) los ntawm cov txheej txheem ntawm (a), nws yuav siv cov adenosine triphosphate raw cov ntaub ntawv nyob rau hauv lub party nucleus los luam thiab synthesize nws. tus kheej cov khoom siv caj ces thiab cov khoom siv uas yuav tsum tau muaj rau kev sib txuas ntawm cov protein, xws li tub txib RNAThen, tus tub txib RNA yog siv los ua kom nws cov protein ntau (xws li cov txheej txheem (k) hauv daim duab) hauv qab catalysis ntawm ntau yam enzymes (xws li 3C protease) hauv lub host cell thiab kev pab ntawm raw cov ntaub ntawv los tsim lub plhaub. Txog tam sim no, tus kab mob no tau ua tiav kev tsim tawm. Tom qab tus kab mob nkag mus rau hauv lub xov tooj ntawm tes, nws yuav rov ua dua thiab sib txuas ntau cov kab mob zoo sib xws, tshem tawm cov khoom siv ntawm tes ntawm tus tswv tsev kom txog thaum lub cell qub puas thiab tawg. Txawm li cas los xij, lub cev yog tsim los ntawm cov hlwb. Yog hais tias lub hlwb raug rhuav tshem ntawm qhov loj, cov kab mob yuav pom cov kab mob pathological.
Kev sib tham txog kev sim tshuaj
Cov kev sim qhia tias gs-441524 muaj txiaj ntsig zoo dua li gc376 rau qhov tshwm sim FIP.
Nws tau pom tias gs-441524 tuaj yeem ncav cuag lub qhov muag thiab lub hauv nruab nrab lub paj hlwb los ntawm cov ntshav qhov muag thiab cov ntshav- lub hlwb thaiv. Piv nrog rau 20 tus miv kho nrog gc376, tsuas yog 6 tus miv tseem tsis muaj kab mob tom qab ntau tshaj 18 lub hlis. Cov txiaj ntsig kho mob ntawm gs-441524 yog qhov zoo tshaj plaws, nrog kev siv tshuaj tsawg dua thiab kev kho mob luv dua.
Los ntawm cov saum toj no, peb tuaj yeem pom tias Gs-441524 ua haujlwm ntawm theem rov ua dua ntawm cov khoom siv caj ces ua raws li tus neeg sib tw ntawm ntuj nucleoside triphosphate thiab koom nrog kev rov ua dua ntawm miv coronavirus RNA. Thaum lub gs-441524 molecule tau muab tso rau hauv tus kab mob RNA, qhov kev rov ua dua yuav ua tsis tiav, thaiv cov synthesis ntawm miv coronavirus RNA los ntawm lub hauv paus, thiab tseem cuam tshuam rau kev sib txuas ntawm miv coronavirus plhaub protein tom qab. Nws ua rau theem (d) hauv daim duab saum toj no.
Gc376 lub hom phiaj 3C protease thiab muab nws nrog 3C protease los cuam tshuam lub luag haujlwm ntawm C protease hauv synthesis ntawm miv cov kab mob khaub thuas protein. Nws tsuas tuaj yeem ua rau theem synthesis ntawm lub tsho tiv no protein, uas yog, txheej txheem (k) hauv daim duab.
Txawm li cas los xij, feem ntau, cov nucleoside analog gs-441524 tseem muaj kev cia siab zoo hauv kev kho mob ntawm qhov tshwm sim FIP. Nws cia siab tias qhov kev tshawb fawb no tuaj yeem siv rau hauv tsev kho mob sai li sai tau thiab tawg los ntawm kev thaiv qhov FIP tsis tuaj yeem kho. Peb tseem yuav ua tib zoo mloog cov kev tshawb fawb tiam sis thiab hloov kho lawv rau koj raws sijhawm.