KEAP1/NRF2 kao potencijalno ciljno mesto dejstva lekova

  • Albena Dinkova-Kostova University of Dundee, School of Medicine, Division of Cellular Medicine; Johns Hopkins University School of Medicine, Department of Pharmacology and Molecular Sciences and Department of Medicine
Ključne reči: Elektrofil, KEAP1, NQO1, NRF2, omaveloksolon, sulforafan

Sažetak


Nuklearni faktor 2 povezan sa nuklearnim faktorom eritroidom 2 (NRF2, koga kodira NFE2L2) je inducibilni transkripcioni faktor koji reguliše ekspresiju široke mreže gena koji kodiraju proteine sa citoprotektivnim funkcijama. NRF2 takođe ima i ulogu u održavanju mitohondrijske i proteinske homeostaze, a njegova aktivacija omogućava adaptaciju na različite vrste ćelijskog stresa. NRF2 je regulisan pre svega na nivou stabilnosti proteina pomoću tri glavna sistema ubikvitin ligaze, pri čemu je najbolje proučena regulacija putem proteina KEAP1, supstratnog adaptera za Cul3/Rbx1-zavisnu ubikvitin ligazu. KEAP1 je multifunkcionalni protein koji, pored toga što je supstratni adapter, predstavlja i senzor za elektrofile i oksidante. Farmakološka inaktivacija proteina KEAP1 ima zaštitni efekat kod životinjskih modela korišćenih za ispitivanje oboljenja koja pogađaju ljude, te je stoga danas prepoznat kao ciljno mesto delovanja lekova, posebno kada je reč o hroničnim oboljenjima kod kojih su oksidativni stres i inflamacija u osnovi patogeneze. Razvijena su brojna jedinjenja usmerena na KEAP1, uključujući elektrofile koji se kovalentno vezuju za cisteinske senzore u KEAP1, neelektrofilne inhibitore protein-protein interakcija koji se vezuju za Kelch domen KEAP1, prekidajući njegovu interakciju sa NRF2, a nedavno i heterobifunkcionalne himere usmerene na proteolizu (PROTACs) koje podstiču proteazomsku razgradnju KEAP1. Razvoj lekova koji sadrže jedinjenja usmerena na KEAP1 doveo je do uvođenja dva jedinjenja, dimetil fumarata (BG-12, Tecfidera®) i RTA-408 (omaveloksolon, SKYCLARYS®), u kliničku praksu. Dimetil fumarat je 2013. odobren kao prvi oralni agens u prvoj liniji lečenja relapsno-remitentne multiple skleroze, a koristi se i u terapiji umerene do jake plak psorijaze. U februaru 2023. godine, američka Uprava za hranu i lekove (FDA) odobrila je omaveloksolon kao prvi i jedini lek namenjen pacijentima obolelim od Fridrajhove ataksije.

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Objavljeno
2023/04/26
Rubrika
Pregledni (Revijalni) rad