Ho Ntlafatsa Katleho ea PROTAC: Phuputso e Feto-fetohang
Tšebeliso ea limolek'hule tse nyane tse senyang, tse kang PROTACs (PROteolysis TARgeting Chimeras), e emela leano le lecha la phekolo ka ho susumetsa ho senyeha ka potlako ha liprotheine tse bakang mafu. Mokhoa ona o fana ka tataiso e ncha e tšepisang bakeng sa kalafo ea mafu a fapaneng, ho kenyeletsoa le kankere.
Tsoelo-pele e kholo tšimong ena e sa tsoa hatisoa koranteng ea Nature Communications ka la 2 Phupu. Phuputso ena, e etelletsoeng pele ke sehlopha sa bafuputsi, e hlwaile litsela tse 'maloa tsa ho supa lisele tse laolang ho senyeha ho reriloeng ha liprotheine tsa bohlokoa tse kang BRD4, BRD2/3, le CDK9 ho sebelisoa li-PROTAC.
Ho fumana hore na litsela tsena tsa tlhaho li ama ho senyeha ha protheine joang, bafuputsi ba ile ba hlahloba liphetoho ho senyehang ha BRD4 boteng kapa bo sieo ba MZ1, e leng BRD4 PROTAC e thehiloeng ho CRL2VHL. Liphuputso li bontšitse hore litsela tse fapaneng tsa tlhaho tsa sele li ka thibela ho senyeha ho reriloeng ke BRD4 ka bohona, e leng se ka hanyetsoang ke lithibela-mafu tse itseng.
Liphihlelo tsa Bohlokoa: Bafuputsi ba netefalitse metsoako e 'maloa e le lintho tse ntlafatsang ho senyeha ha lisele, ho kenyeletsoa le PDD00017273 (sethibela-PARG), GSK2606414 (sethibela-PERK), le luminespib (sethibela-HSP90). Liphetho tsena li bontša hore litsela tse ngata tsa tlhaho tsa sele li ama katleho ea ho senyeha ha protheine mehatong e fapaneng.
Liseleng tsa HeLa, ho ile ha hlokomeloa hore thibelo ea PARG ke PDD e ka ntlafatsa haholo ho senyeha ho reriloeng ha BRD4 le BRD2/3 empa eseng ha MEK1/2 kapa ERα. Tlhahlobo e 'ngoe e senotse hore thibelo ea PARG e khothalletsa ho thehoa ha BRD4-MZ1-CRL2VHL ternary complex le ubiquitination e hokahaneng le K29/K48, ka hona ho nolofatsa ts'ebetso ea ho senyeha. Ho feta moo, thibelo ea HSP90 e fumanoe e ntlafatsa ho senyeha ha BRD4 kamora ubiquitination.
Temohisiso ea Mekaniki: Phuputso e hlahlobile mekhoa e thehiloeng liphellong tsena, e senola hore li-inhibitor tsa PERK le HSP90 ke litsela tsa mantlha tse susumetsang ho senyeha ha protheine ka sistimi ea ubiquitin-proteasome. Li-inhibitor tsena li fetola mehato e fapaneng ts'ebetsong ea ho senyeha ho bakoang ke metsoako ea lik'hemik'hale.
Ho feta moo, bafuputsi ba batlisisitse hore na di-enhancer tsa PROTAC di ka eketsa bokgoni ba di-degrader tse matla. SIM1, PROTAC e sa tswa ntshetswa pele ka trivalent, e bontshitswe e susumetsa ka katleho ho thehwa ha motsoako wa BRD-PROTAC-CRL2VHL mme ya senya BRD4 le BRD2/3 ka mora moo. Ho kopanya SIM1 le PDD kapa GSK ho bakile lefu le sebetsang hantle ho feta ho sebedisa SIM1 feela.
Phuputso e boetse e fumane hore thibelo ea PARG e ka senya eseng feela liprotheine tsa lelapa la BRD empa hape le CDK9 ka katleho, e leng se bontšang hore liphuputso tsena li ka sebelisoa ka bongata.
Litlamorao tsa Nakong e Tlang: Bangoli ba phuputso ba lebelletse hore litlhahlobo tse ling li tla khetholla litsela tse ling tsa lisele tse tlatsetsang kutloisisong ea mekhoa e reretsoeng ea ho senyeha ha protheine. Litemohisiso tsena li ka lebisa nts'etsopele ea maano a phekolo a sebetsang haholoanyane bakeng sa mafu a fapaneng.
Referense: Yuki Mori le ba bang. Litsela tsa matšoao a ka hare li laola ho senyeha ha protheine e reriloeng. Nature Communications (2024). sengoloa se felletseng https://www.nature.com/articles/s41467-024-49519-z
Phuputso ena e ncha e totobatsa bokhoni ba PROTAC lits'ebetsong tsa kalafo mme e totobatsa bohlokoa ba ho utloisisa litsela tsa ho fetisa melaetsa ea sele ho ntlafatsa katleho ea ho senyeha ha protheine e reriloeng.