Ukuthuthukisa Ukusebenza Kahle Kwe-PROTAC: Ucwaningo Oluqabulayo
Ukusetshenziswa kwezinto ezincane ezinciphisa ama-molecule, njenge-PROTACs (PROteolysis TARgeting Chimeras), kumelela isu elisha lokwelapha ngokubangela ukuwohloka okusheshayo kwamaprotheni abangela izifo. Le ndlela inikeza isiqondiso esisha esithembisayo sokwelashwa kwezifo ezahlukahlukene, okuhlanganisa nomdlavuza.
Intuthuko ebalulekile kulo mkhakha isanda kushicilelwa kumagazini i-Nature Communications ngoJulayi 2. Ucwaningo, oluholwa yithimba labacwaningi, luthole izindlela eziningana zokuthumela izimpawu zamaseli ezilawula ukuwohloka okuqondiwe kwamaprotheni abalulekile njenge-BRD4, i-BRD2/3, kanye ne-CDK9 kusetshenziswa ama-PROTAC.
Ukuze kutholakale ukuthi lezi zindlela zangaphakathi zithinta kanjani ukuwohloka kwamaprotheni, abacwaningi bahlole izinguquko ekuwohlokeni kwe-BRD4 lapho kukhona noma kungekho khona i-MZ1, i-BRD4 PROTAC esekelwe ku-CRL2VHL. Okutholakele kubonise ukuthi izindlela ezahlukene zangaphakathi zamaseli zingase zivimbele ngokuzenzakalelayo ukuwohloka okuqondiswe ku-BRD4, okungalwiwa yizithibi ezithile.
Okutholakele Okubalulekile: Abacwaningi baqinisekise ama-compound amaningana njengezithuthukisi zokubola, okuhlanganisa i-PDD00017273 (i-PARG inhibitor), i-GSK2606414 (i-PERK inhibitor), kanye ne-luminespib (i-HSP90 inhibitor). Le miphumela ikhombisa ukuthi izindlela eziningi zangaphakathi zamaseli zithinta ukusebenza kahle kokubola kwamaprotheni ngezinyathelo ezahlukene.
Kumaseli e-HeLa, kwabonwa ukuthi ukuvinjelwa kwe-PARG yi-PDD kungathuthukisa kakhulu ukuwohloka okuqondiwe kwe-BRD4 kanye ne-BRD2/3 kodwa hhayi kwe-MEK1/2 noma i-ERα. Ukuhlaziywa okwengeziwe kwembule ukuthi ukuvinjelwa kwe-PARG kukhuthaza ukwakheka kwe-BRD4-MZ1-CRL2VHL ternary complex kanye ne-K29/K48-linked ubiquitination, ngaleyo ndlela kube lula inqubo yokuwohloka. Ngaphezu kwalokho, ukuvinjelwa kwe-HSP90 kwatholakala kuthuthukisa ukuwohloka kwe-BRD4 ngemva kokuwohloka kwe-ubiquitination.
Ukuqonda Kwemishini: Ucwaningo luhlole izindlela ezisekela le miphumela, lwembula ukuthi ama-PERK kanye nama-HSP90 inhibitors ayizindlela eziyinhloko ezithonya ukuwohloka kwamaprotheni ngohlelo lwe-ubiquitin-proteasome. Lawa ma-inhibitor alawula izinyathelo ezahlukene enkambisweni yokuwohloka ebangelwa ama-chemical compounds.
Ngaphezu kwalokho, abacwaningi baphenye ukuthi izithuthukisi ze-PROTAC zingakhuphula yini ukusebenza kahle kwezihlaseli ezinamandla. I-SIM1, i-PROTAC esanda kuthuthukiswa ephindwe kathathu, iboniswe ukuthi ikhuthaza ukwakheka kwe-BRD-PROTAC-CRL2VHL complex kanye nokuwohloka okulandelayo kwe-BRD4 kanye ne-BRD2/3. Ukuhlanganisa i-SIM1 ne-PDD noma i-GSK kuholele ekufeni kwamaseli okusebenza kahle kakhulu kunokusebenzisa i-SIM1 yodwa.
Ucwaningo luphinde lwathola ukuthi ukuvinjelwa kwe-PARG kungalimaza ngempumelelo hhayi amaprotheni omndeni we-BRD kuphela kodwa futhi ne-CDK9, okuphakamisa ukusebenza okubanzi kwalokhu okutholakele.
Imiphumela Yesikhathi Esizayo: Abalobi balolu cwaningo balindele ukuthi ukuhlolwa okwengeziwe kuzokhomba izindlela ezengeziwe zamaseli ezifaka isandla ekuqondeni izindlela eziqondiwe zokuqothulwa kwamaprotheni. Lokhu kuqonda kungaholela ekuthuthukisweni kwamasu okwelapha asebenza kahle kakhulu ezinhlobonhlobo zezifo.
Ireferensi: UYuki Mori nabanye. Izindlela zokubonisana zangaphakathi zilawula ukuwohloka kwamaprotheni aqondiwe. I-Nature Communications (2024). isihloko esigcwele https://www.nature.com/articles/s41467-024-49519-z
Lolu cwaningo oluphumelelayo lugcizelela amandla e-PROTAC ekusetshenzisweni kwezokwelapha futhi lugcizelela ukubaluleka kokuqonda izindlela zokuthumela izimpawu zamaseli ukuze kuthuthukiswe ukusebenza kahle kokuwohloka kwamaprotheni okuqondiwe.