Kongera imikorere ya PROTAC: Inyigo Ifatika
Gukoresha utunyangingo duto two kwangiza imiterere y’umubiri, nka PROTACs (PROteolysis TARgeting Chimeras), ni ingamba nshya zo kuvura binyuze mu gutuma poroteyine zitera indwara zigabanuka vuba. Ubu buryo butanga icyerekezo gishya cyizewe cyo kuvura indwara zitandukanye, harimo na kanseri.
Iterambere rikomeye muri uru rwego riherutse gusohoka mu kinyamakuru Nature Communications ku ya 2 Nyakanga. Ubushakashatsi, buyobowe n'itsinda ry'abashakashatsi, bwagaragaje inzira nyinshi zo gutanga ibimenyetso ku turemangingo zigenga kwangirika kwa poroteyine z'ingenzi nka BRD4, BRD2/3, na CDK9 hakoreshejwe PROTACs.
Kugira ngo bamenye uburyo izi nzira z’ibanze zigira ingaruka ku kwangirika kwa poroteyine, abashakashatsi basuzumye impinduka mu kwangirika kwa BRD4 mu gihe hari cyangwa hatari MZ1, BRD4 PROTAC ishingiye kuri CRL2VHL. Ibyavuye mu bushakashatsi byagaragaje ko inzira zitandukanye z’uturemangingo zishobora gukumira kwangirika kwa BRD4, bishobora kurwanywa n’ibintu byihariye bishobora gukumira.
Ibyavumbuwe by'ingenzi: Abashakashatsi bemeje ko ibintu byinshi bitera kwangirika kw'umubiri, birimo PDD00017273 (umuti ugabanya ubukana bwa PARG), GSK2606414 (umuti ugabanya ubukana bwa PERK), na luminespib (umuti ugabanya ubukana bwa HSP90). Ibi bisubizo bigaragaza ko inzira nyinshi z'uturemangingo zigira ingaruka ku buryo poroteyine yangirika mu ntambwe zitandukanye.
Mu turemangingo twa HeLa, byagaragaye ko gukumira PARG na PDD bishobora kongera cyane ukwangirika kwa BRD4 na BRD2/3 ariko ntibigere kuri MEK1/2 cyangwa ERα. Isesengura ryinyongera ryagaragaje ko gukumira PARG bitera ishingwa rya BRD4-MZ1-CRL2VHL ternary complex na K29/K48-linked ubiquitination, bityo bigafasha mu kwangirika. Byongeye kandi, gukumira HSP90 byagaragaye ko kongera kwangirika kwa BRD4 nyuma ya ubiquitination.
Ibisobanuro bya tekiniki: Ubushakashatsi bwasuzumye uburyo izi ngaruka zibaho, bugaragaza ko imiti ibuza PERK na HSP90 ari inzira z'ibanze zigira ingaruka ku kwangirika kwa poroteyine binyuze muri sisitemu ya ubiquitin-proteasome. Iyi miti ibuza ihindura intambwe zitandukanye mu nzira yo kwangirika guterwa n'ibinyabutabire.
Byongeye kandi, abashakashatsi bakoze ubushakashatsi ku bijyanye no kumenya niba PROTAC enhancers zishobora kongera ubushobozi bw'ibikoresho bigabanya ubukana bw'ibinyabutabire. SIM1, PROTAC iherutse gukorwa ifite ubukana butatu, byagaragaye ko ituma habaho BRD-PROTAC-CRL2VHL complex neza, bityo BRD4 na BRD2/3 bikangirika. Guhuza SIM1 na PDD cyangwa GSK byatumye uturemangingo twicwa neza kurusha gukoresha SIM1 gusa.
Ubushakashatsi bwagaragaje kandi ko gukumira PARG bishobora kwangiza poroteyine zo mu muryango wa BRD ndetse na CDK9, bigaragaza ko ibi byavumbuwe bifite akamaro kanini.
Ingaruka z'ejo hazaza: Abanditsi b'ubushakashatsi bateganya ko isuzuma rirambuye rizagaragaza izindi nzira z'uturemangingo zigira uruhare mu gusobanukirwa uburyo bwo kwangiza poroteyine. Ubu buhanga bushobora gutuma habaho ingamba nziza zo kuvura indwara zitandukanye.
Icyitonderwa: Yuki Mori n'abandi. Inzira zo gutanga ibimenyetso zigenga iyangirika rya poroteyine. Nature Communications (2024). inkuru yuzuye https://www.nature.com/articles/s41467-024-49519-z
Ubu bushakashatsi bugaragaza ubushobozi bwa PROTAC mu mikorere y’ubuvuzi kandi bugaragaza akamaro ko gusobanukirwa inzira zo gutanga amakuru ku turemangingo kugira ngo hongerwe uburyo bwo kwangirika kwa poroteyine.