Suiga Peptide
Peptides Stapled
O le a le Stapled Peptides?
O suʻesuʻega ua faʻaalia ai o peptides e iai le α-helical structure ma le tamaoaiga i le tau lelei e mafai ona sopoia sela sela. Peitai, i le taimi na vavae ese ai mai le tino matua, e le mafai e le peptide ona faatumauina lona fausaga lona lua muamua, ma o le le mautu o le conformational e taitai atu ai i le vaivai o lona fusia i polotini, ae o peptides laina masani e le mafai ona sopoia le membrane sela ma faigofie ona faʻafefeteina. Ina ua uma taumafaiga faifai pea, Verdine et al. fausia se fausaga fou o le peptide, o lenei peptide e taʻua o le stapled peptide, o se fatafata uma-carbon ma fausaga α-helical, fa'a-carbon scaffold fa'amautu le fausaga α-helical, lea e faʻamalosia ai le fegalegaleaiga i le va o peptide molecules ma polotini, ma stapled peptide e mafai ona sopoia le membrane sela ma e le faigofie ona hydrolysed, lea e maualuga atu le gaioiga fa'afoma'i pe a fa'atusatusa i vaila'au mole-moli-mole muamua ma vaila'au fa'avae polotini. gaioiga fa'afoma'i maualuga atu nai lo vaila'au mole mole laiti muamua ma vaila'au polotini.
Stapled Peptides faasaienisi
O le eseesega i le va o le tuʻufaʻatasiga o le peptide faʻapipiʻiina ma le faʻaogaina o le peptide masani o loʻo taoto i le faʻaofiina o ni amino acids e lua e le masani ai o loʻo i ai vaega α-methyl ma α-alkenyl i le taimi o le faʻaogaina o le peptide filifili., ona tupu ai lea o le olefinic fa'alavelave fa'aleagaina i le va o amino acids e le fa'alenatura e fausia ai se fa'a-carbon scaffold ma mautu α-helical conformation., ona fa'apipi'i lea o le peptide fa'amau.
Stapled Peptide Chemistry
Le Grubbs fa'ato'aga muamua (taumatau) faʻatasi ai ma tricyclohexylphosphine (PCy3) ligands ma apical positioned carbene carbon o se faʻalavelave faʻamautu ruthenium faʻaaogaina mo le olefin metathesis i peptides.. O suʻesuʻega mulimuli ane na taʻitaʻia ai le mamanu o se Grubbs faʻamautu lona lua faʻamalosi faʻamalosi. (ogatotonu). O se fa'aupuga lona tolu, ua lauiloa foi o le Hoveyda–Grubbs catalyst (tauagavale), sui le N-heterocyclic carbene ligand mo se benzylidene ligands o loʻo i ai se vaega chelating ortho-isopropoxy faʻapipiʻi i le mama benzene.
Ga'i peptide fa'apipi'i tasi
Ga'i peptide fa'apipi'i tasi. Le tuufaatasia o le alpha-4-n-pentenylalanine e lua (S5) toega i totonu o se peptide strand e mafai ai le metathesis tapuni-mama (i.e., Grubbs tali) e fatu ai se peptide e tasi. Pe a n = 3 (i.e. ma 3 amino acids i le va o toega S5) o le ituaiga autu e lauiloa o le i, i + 4.
Fa'atonuga Ta'itasi
Le maualuga maualuga ma le agamalu tulaga o le "kiliki" tali (Huisgen 1,3-dipolar cycloaddition fa'a'a'amea fa'a'apa) faʻatasi ma le faigofie o le faʻapipiʻiina o mea amino e le masani ai, e mafai ai ona fa'afaigofie le fa'apipi'iina o peptide fa'apipi'i triazole. Faataitaiga, se tuufaatasiga o L- E mafai (εN3) ma D-Pra (D-propargylalanine) sui i le i ma le i + 4 tulaga e mafai ona faʻaaogaina mo le faʻatupuina o peptides triazole-stapled tasi..
Fa'amatalaga Fa'apitoa
Fuafua-tulafono mo peptides faʻapipiʻi faʻatasi ma in vivo gaioiga ma latou faʻaoga i Mdm2/X antagonists.
E ui lava o peptides α-helical faʻapipiʻi e mafai ona faʻafeiloaʻi sini luʻitau, o lo latou alualu i luma e faʻalavelaveina e le le lelei o le malamalama mo le faʻaogaina o latou sela aʻo aloese mai mea oona. E ala i le tuufaatasia >350 molelaula, matou te tu'uina atu fa'asologa o galuega mo le fa'ailoaina o peptide fa'apipi'i fa'asaga ia Mdm2(X) fa'atasi ai ma gaioiga in vivo ma leai ni a'afiaga e le fa'atatauina. O faʻamatalaga autu e aofia ai se faʻasalalauga manino i le va o le lipophility ma le faʻaogaina, ave'esea o moliaga lelei e alofia ai mea oona e le taula'i, fa'amanino le tu'uina o toega anionic e fa'aleleia atili ai le solubility/amio, optimization o C-terminal umi / helicity e faʻaleleia le malosi, ma le fa'asilisiliina ole ituaiga/numera fa'atosina e alofia ai le polypharmacology. O le faʻaogaina o galuega e tuʻuina atu ai peptides ma >292x fa'aleleia le malosi o le fa'atuputeleina o sela ma leai ni a'afiaga o le fa'atuputeleina o sela ( > 3800x i luga o le fa'asino igoa). Fa'aogaina o nei 'tulafono mamanu' i se Mdm2 ma'oti(X) peptide faasologa faʻaleleia ( > 150x) malosi feavea'i ma aveese mea oona i fafo. Ole fa'asologa o galuega e tatau ona fa'afaigofieina a'afiaga o togafitiga, aemaise lava mo na sini e pei ole Mdm2(X) o lo'o i ai feso'ota'iga hydrophobic ma e mafai ona fa'atatauina i se fa'ama'i fa'ama'i.
Au'aunaga Feso'ota'i Peptide Suiga
peptide glycosylation
peptide glycosylation
Peptide glycosylation o se suiga faʻapipiʻi e mafai ona faʻaleleia atili ai mea faʻapitoa o peptides.
Faitau atilipeptide Phosphorylation
peptide Phosphorylation
E mafai ona tupu le Phosphoralation ile Serine (S, Pe 'a), Threonine (T, Thr) ma Tyrosine (Y, Tyr) filifili itu e ala i le fausia o fusi phosphoester
Faitau atiliPeptides Stapled
Peptides Stapled
Folasaga o ni amino acids e lua e iai le α-methyl, vaega α-alkenyl i le taimi o le fa'amaopoopoina o filifili peptide.
Faitau atiliCyclic Peptide
Cyclic Peptide
O le ta'amilosaga peptide e fa'aleleia ai le mautu o peptide (fa'atatau i a latou analogues linear) ma o se taʻiala masani i le atinaʻeina o peptide.
Faitau atilisuiga ole peptide
Le poto masani i le peptide suiga, saunia le tele o auala talafeagai mo suʻesuʻega peptide.
