Liphetoho tsa Peptide
Li-peptide tse tloaelehileng
Stapled Peptides ke eng?
Liphuputso li bontšitse hore li-peptide tse nang le sebopeho sa α-helical le tefiso e ngata e ntle li ka tšela lisele tsa lisele. Leha ho le joalo, hang ho arohana le sehlopha sa motsoali, peptide e ke ke ea boloka sebopeho sa eona sa pele sa bobeli, 'me ho se tsitse ha conformational ho lebisa ho fokotseng ho tlama ha eona ho liprotheine, athe li-peptide tse tloaelehileng tse melang ha li khone ho tšela lera la sele 'me li na le hydrolysed habonolo. Ka mor'a liteko tse sa khaotseng, Verdine et al. e hlahisitse sebopeho se secha sa peptide, peptide ena e bitsoa stapled peptide, ke scaffold ea carbon eohle e nang le sebopeho sa α-helical, all-carbon scaffold e tsitsisa sebopeho sa α-helical, e matlafatsang tšebelisano lipakeng tsa limolek'hule tsa peptide le liprotheine, 'me peptide ea stapled e ka tšela lera la sele 'me ha ho bonolo ho etsoa ka hydrolysed, e nang le ts'ebetso e phahameng ea pharmacological ha e bapisoa le lithethefatsi tsa pele tsa molek'hule e nyane le litlhare tse thehiloeng ho protheine. ts'ebetso e phahameng ea pharmacological ho feta lithethefatsi tsa molek'hule tse nyane tse fetileng le lithethefatsi tsa protheine.
Saense ea Stapled Peptides
Phapang lipakeng tsa motsoako oa stapled peptide le peptide synthesis e tloaelehileng e ho kenyelletsoa ha li-amino acid tse peli tseo e seng tsa tlhaho tse nang le lihlopha tsa α-methyl le α-alkenyl nakong ea motsoako o tiileng oa ketane ea peptide., ebe olefinic complex decomposition reaction e etsahala lipakeng tsa li-amino acid tse peli tseo e seng tsa tlhaho ho etsa scaffold ea khabone e nang le α-helical conformation e tsitsitseng., ebe o kopanya peptide ea stapled.
Khemistri ea Peptide ea Stapled
Moloko oa pele oa Grubbs catalyst (letsetsoa) ka tricyclohexylphosphine (PCy3) ligands le apical positioned carbene carbon ke ruthenium complex e batlang e tsitsitse e sebelisoang bakeng sa olefin metathesis ka li-peptide.. Liphuputso tse ileng tsa latela li ile tsa lebisa ho thehoeng ha mokelikeli o tsitsitseng haholoanyane oa moloko oa bobeli oa Grubbs. (bohareng). Mokokotlo oa 3rd catalyst, e boetse e tsejoa e le catalyst ea Hoveyda–Grubbs (hantle), e nkela sebaka sa N-heterocyclic carbene ligand bakeng sa ligand tsa benzylidene tse nang le sehlopha sa chelating ortho-isopropoxy se kopantsoeng le reng ea benzene..
Karabelo e le 'ngoe ea stapled peptide
Karabelo e le 'ngoe ea stapled peptide. Ho kenyelletsoa ha li-alpha-4-n-pentenylalanine tse peli (S5) mesaletsa ka har'a khoele ea peptide e nolofalletsa metathesis ea ho koala mehala (i.e., Boitšoaro ba Grubbs) ho theha peptide e le 'ngoe ea stapled. Ha n = 3 (i.e. ka 3 amino acid pakeng tsa masala a S5) mofuta oa mantlha o tsejoa e le i, ke + 4.
Litlhophiso tsa Single Staple
Bokhoni bo phahameng le maemo a bonolo a ho arabela ka "tobetsa". (Copper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction) ho kopantsoe le boiketlo ba ho kopanya li-amino acid tse hlokahalang tseo e seng tsa tlhaho, e lumella hore ho be bonolo ho kopanya li-peptide tse nang le triazole. Ka mohlala, motsoako oa L- Ka (eN3) le D-Pra (D-propargylalanine) e kentsoeng sebakeng sa i le i+4 e ka sebelisoa bakeng sa ho hlahisa li-peptide tse nang le triazole-stapled..
Litlhaloso tse hlahang
Melao ea moralo bakeng sa li-peptide tse tiisitsoeng tse nang le ts'ebetso ea in vivo le ts'ebeliso ea tsona ho bahanyetsi ba Mdm2/X.
Le hoja li-peptide tsa α-helical li ka sebetsana le lipehelo tse thata, tsoelo-pele ea bona e sitisoa ke kutloisiso e fokolang ea ho etsa hore lisele li kenellehe ha li ntse li qoba chefo e sa lebelloang.. Ka ho kopanya >350 limolek'hule, re hlahisa li-workflows tsa ho tsebahatsa li-peptide tsa stapled khahlano le Mdm2(X) e nang le ts'ebetso ea in vivo mme ha e na litlamorao tse sa lebelloang. Litlhaloso tsa bohlokoa li kenyelletsa kamano e hlakileng pakeng tsa lipophilicity le permeability, ho tlosa tefiso e ntle ho qoba chefo e sa lebelloang, ho beoa ka bohlale ha masala a anionic ho ntlafatsa ho qhibiliha/boitšoaro, optimization ea bolelele ba C-terminal / helicity ho matlafatsa potency, le optimization ea mofuta oa mantlha/nomoro ho qoba polypharmacology. Ts'ebeliso ea phallo ea mosebetsi e fana ka li-peptide ka >292x e ntlafalitse matla a ho ata ha lisele le ho se be le litlamorao tsa ho ata ha lisele ( > 3800x index ea sepheo). Tšebeliso ea 'melao ena ea moralo' ho Mdm2 e ikhethileng(X) letoto la peptide lea ntlafala ( > 150x) matla a cellular le ho tlosa chefo e sa lebelloang. Ts'ebetso e hlalositsoeng e lokela ho thusa litlamorao tsa kalafo, haholoholo bakeng sa lipehelo tse joalo ka Mdm2(X) tse nang le li-interface tsa hydrophobic mme li ka shejoa ka sepheo sa helical.
Litšebeletso tse Amanang tsa Phetoho ea Peptide
glycosylation ea peptide
glycosylation ea peptide
Peptide glycosylation ke phetoho e kopanetsoeng e ka ntlafatsang thepa ea physicochemical ea peptide.
Bala haholoanyanePhosphorylation ea peptide
Phosphorylation ea peptide
Phosphoralation e ka hlaha ka Serine (S, Ho ba), Threonine (T, Thr) le Tyrosine (Y, Tyr) liketane tse mahlakoreng ka ho theha bond ea phosphoester
Bala haholoanyaneLi-peptide tse tloaelehileng
Li-peptide tse tloaelehileng
Kenyelletso ea li-amino acid tse peli tseo e seng tsa tlhaho tse nang le α-methyl, lihlopha tsa α-alkenyl nakong ea motsoako o tiileng oa liketane tsa peptide.
Bala haholoanyanePeptide ea cyclic
Peptide ea cyclic
Peptide cyclization e ntlafatsa botsitso ba li-peptide (e amanang le li-analogue tsa bona tsa mela) 'me ke leano le tloaelehileng ho nts'etsopele ea peptide.
Bala haholoanyanephetoho ea peptide
Boiphihlelo bo pharalletseng ba phetoho ea peptide, ho fana ka mekhoa e mengata e sebetsang ea lipatlisiso tsa peptide.
