Kuvandudza Kushanda kwePROTAC: Chidzidzo Chinobaya Mwoyo
Kushandiswa kwezvinhu zvinoderedza mamorekuru madiki, zvakaita sePROTACs (PROteolysis TARgeting Chimeras), inzira itsva yekurapa nekukurumidzisa kuparara kwemapuroteni anokonzera zvirwere. Nzira iyi inopa nzira itsva inovimbisa yekurapa zvirwere zvakasiyana-siyana, kusanganisira kenza.
Kufambira mberi kukuru mubasa iri kwakaburitswa munguva pfupi yapfuura mumagazini yeNature Communications musi wa2 Chikunguru. Chidzidzo ichi, chakatungamirwa nechikwata chevaongorori, chakaona nzira dzakasiyana-siyana dzekutumira masaini mumasero dzinodzora kuparara kwemapuroteni akakosha akadai seBRD4, BRD2/3, uye CDK9 vachishandisa maPROTAC.
Kuti vaone kuti nzira idzi dzemukati dzinokanganisa sei kuora kwemapuroteni, vaongorori vakaongorora shanduko mukuora kweBRD4 kana paine kana kusavapo kweMZ1, iyo CRL2VHL-based BRD4 PROTAC. Zvakawanikwa zvakaratidza kuti nzira dzakasiyana-siyana dzemukati dzemasero dzinogona kudzivirira kuora kweBRD4, izvo zvinogona kudziviswa nezvinodzivisa.
Zvakawanikwa Zvikuru: Vaongorori vakasimbisa mishonga yakati wandei semishonga inosimudzira kuora kwemasero, kusanganisira PDD00017273 (PARG inhibitor), GSK2606414 (PERK inhibitor), uye luminespib (HSP90 inhibitor). Izvi zvinoratidza kuti nzira dzakawanda dzemukati memasero dzinokanganisa kushanda kwekuparadzwa kweprotein pamatanho akasiyana.
Mumasero eHeLa, zvakaonekwa kuti kudziviswa kwePARG nePDD kunogona kuwedzera zvakanyanya kuderedzwa kwakanangana kweBRD4 neBRD2/3 asi kwete kweMEK1/2 kana ERα. Ongororo yakawedzerwa yakaratidza kuti kudziviswa kwePARG kunokurudzira kuumbwa kweBRD4-MZ1-CRL2VHL ternary complex uye K29/K48-linked ubiquitination, nokudaro zvichiita kuti kuderedzwa kuwedzere. Pamusoro pezvo, kudziviswa kweHSP90 kwakawanikwa kuchisimudzira kuderedzwa kweBRD4 mushure mekuderedzwa kweubiquitination.
Ruzivo rweMakanika: Chidzidzo ichi chakaongorora mashandiro anoita mhedzisiro iyi, zvichiratidza kuti PERK neHSP90 inhibitors inzira huru dzinokanganisa kuparara kwemapuroteni kuburikidza neubiquitin-proteasome system. Izvi zvinodzivirira zvinogadzirisa matanho akasiyana mukuora kunokonzerwa nemakemikari.
Uyezve, vaongorori vakaongorora kana zvinosimudzira PROTAC zvingawedzera kushanda kwezvinoparadza zvine simba. SIM1, PROTAC yakagadzirwa nguva pfupi yadarika, yakaratidzwa kuti inokurudzira kuumbwa kweBRD-PROTAC-CRL2VHL complex uye kuora kweBRD4 neBRD2/3 kwakazotevera. Kusanganisa SIM1 nePDD kana GSK kwakaita kuti masero afe zviri nani pane kushandisa SIM1 chete.
Chidzidzo ichi chakawanawo kuti kudziviswa kwePARG kunogona kukanganisa kwete mapuroteni emhuri yeBRD chete asiwo CDK9, zvichiratidza kushanda kwakakura kwezviwanikwa izvi.
Zvichaitika Mune Remangwana: Vanyori vechidzidzo ichi vanofungidzira kuti kuongororwa kwakawanda kucharatidza dzimwe nzira dzemasero dzinobatsira mukunzwisisa nzira dzekuparadza mapuroteni. Izvi zvinogona kutungamira mukugadzirwa kwenzira dzinoshanda dzekurapa zvirwere zvakasiyana-siyana.
Referensi: Yuki Mori nevamwe. Nzira dzemukati dzekutumira zviratidzo dzinogadzirisa kuora kwemapuroteni akatarwa. Nature Communications (2024). chinyorwa chakazara https://www.nature.com/articles/s41467-024-49519-z
Chidzidzo ichi chinosimbisa kugona kwePROTACs mukurapa uye chinosimbisa kukosha kwekunzwisisa nzira dzekutumira masaini emasero kuti kuwedzere kushanda kwekuparadzwa kwemapuroteni kwakanangana.