Ukuphucula ukusebenza kakuhle kwePROTAC: Uphononongo oluQhubayo
Ukusetyenziswa kwezinto ezinciphisa iimolekyuli ezincinci, ezifana ne-PROTACs (PROteolysis TARgeting Chimeras), kubonisa icebo elitsha lokunyanga ngokubangela ukuwohloka ngokukhawuleza kweeproteni ezibangela izifo. Le ndlela inika indlela entsha ethembisayo yokunyanga izifo ezahlukeneyo, kuquka nomhlaza.
Inkqubela phambili ebalulekileyo kweli candelo ipapashwe kutshanje kwiphephancwadi iNature Communications ngomhla wesi-2 kweyeKhala. Olu phononongo, olukhokelwa liqela labaphandi, luchonge iindlela ezininzi zokubonisana kweeseli ezilawula ukuwohloka okujoliswe kuko kweeproteni eziphambili ezifana neBRD4, BRD2/3, kunye neCDK9 kusetyenziswa iiPROTAC.
Ukuze kuchongwe indlela ezi ndlela zangaphakathi ezichaphazela ngayo ukuwohloka kweproteni, abaphandi bahlolisise utshintsho ekuwohlokeni kweBRD4 xa kukho okanye kungekho MZ1, iBRD4 PROTAC esekwe kwiCRL2VHL. Iziphumo zibonise ukuba iindlela ezahlukeneyo zangaphakathi zeeseli zinokuthintela ngokuzenzekelayo ukuwohloka okujoliswe kwiBRD4, okunokuchaswa zizithinteli ezithile.
Iziphumo eziphambili: Abaphandi baqinisekisile iikhompawundi ezininzi njengeziphuculi zokonakala, kuquka iPDD00017273 (i-PARG inhibitor), iGSK2606414 (i-PERK inhibitor), kunye ne-luminespib (i-HSP90 inhibitor). Ezi ziphumo zibonisa ukuba iindlela ezininzi zeseli ezingaphakathi zichaphazela ukusebenza kakuhle kokonakala kweeproteni ngamanqanaba ahlukeneyo.
Kwiiseli zeHeLa, kwabonwa ukuba ukuthintelwa kwePARG yiPDD kunokuphucula kakhulu ukuthotywa okujoliswe kuko kweBRD4 kunye neBRD2/3 kodwa kungekhona iMEK1/2 okanye i-ERα. Uhlalutyo olongezelelekileyo lutyhile ukuba ukuthintelwa kwePARG kukhuthaza ukwakheka kwe-BRD4-MZ1-CRL2VHL ternary complex kunye ne-K29/K48-linked ubiquitination, ngaloo ndlela kuququzelela inkqubo yokuthotywa. Ukongeza, ukuthintelwa kweHSP90 kufunyenwe kuphucula ukuthotywa kweBRD4 emva kokuthotywa.
Ukuqonda ngoomatshini: Olu phononongo luhlolisise iindlela ezisebenza ngayo ezi ziphumo, lutyhila ukuba ii-PERK kunye nee-HSP90 inhibitors ziindlela eziphambili ezichaphazela ukonakala kweproteni ngenkqubo ye-ubiquitin-proteasome. Ezi zi-inhibitors zilawula amanyathelo ahlukeneyo kwinkqubo yokonakala okubangelwa ziikhemikhali.
Ngaphezu koko, abaphandi baphande ukuba ngaba izithambisi zePROTAC zinokunyusa ukusebenza kakuhle kwezithambisi ezinamandla. I-SIM1, i-PROTAC esandul’ ukuphuhliswa enee-trivalent, ibonakaliswe ukuba ikhuthaza ukwakheka kwe-BRD-PROTAC-CRL2VHL complex kwaye emva koko i-BRD4 kunye ne-BRD2/3 yonakaliswe. Ukudibanisa i-SIM1 ne-PDD okanye i-GSK kubangele ukufa kweeseli okusebenzayo ngakumbi kunokusebenzisa i-SIM1 yodwa.
Olu phononongo lukwafumanise ukuba ukuthintelwa kwePARG kunokonakalisa kungekuphela nje iiproteni zosapho lweBRD kodwa kunye neCDK9, nto leyo ebonisa ukuba ezi ziphumo zisebenza ngokubanzi.
Iziphumo Zexesha Elizayo: Ababhali bolu phononongo balindele ukuba uphononongo olongezelelweyo luya kuchonga iindlela ezongezelelweyo zeeseli ezinegalelo ekuqondeni iindlela ezijoliswe kuzo zokonakala kweeproteni. Ezi ngqiqo zinokukhokelela ekuphuhlisweni kweendlela zonyango ezisebenzayo ngakumbi kwiintlobo ngeentlobo zezifo.
Isalathiso: UYuki Mori nabanye. Iindlela zokubonisa ezingaphakathi zilawula ukuwohloka kweproteni ekujoliswe kuyo. I-Nature Communications (2024). inqaku elipheleleyo https://www.nature.com/articles/s41467-024-49519-z
Olu phononongo oluphambili lugxininisa amandla e-PROTACs kwizicelo zonyango kwaye lugxininisa ukubaluleka kokuqonda iindlela zokuhambisa imiyalezo yeselula ukuphucula ukusebenza kakuhle kokuwohloka kweproteni ekujoliswe kuyo.