Iyezathalidomideyakhunjulwa ngeminyaka yoo-1960 ngenxa yokuba yabangela iziphene ezitshabalalisayo kwiintsana ezisanda kuzalwa, kodwa kwangaxeshanye yayisetyenziswa ngokubanzi ukunyanga i-multiple sclerosis kunye nolunye umhlaza wegazi, kwaye inokuthi, kunye nezalamane zayo zemichiza, ikhuthaze ukutshatyalaliswa kweeseli ezimbini zeeprotheyini ezithile ezingamalungu intsapho yeeprotheni eziqhelekileyo "ezingenazo iziyobisi" (izinto ezibhaliweyo) ezinomzekelo othile we-molecular, i-C2H2 i-zinc finger motif.

Kuphononongo lwakutsha nje olupapashwe kwijenali yezizwe ngezizwe yeSayensi, izazinzulu ezivela kwiMIT Boulder Institute kunye namanye amaziko afumanisa ukuba i-thalidomide kunye neziyobisi ezinxulumeneyo zinokubonelela ngesiqalo kubaphandi ukuba baphuhlise uhlobo olutsha lwekhompawundi yokulwa nomhlaza ekulindeleke ukuba ijolise malunga nama-800. izinto ezikhutshelweyo ezabelana ngesizathu esifanayo. Izinto ezikhutshelweyo zibophelela kwi-DNA kwaye zilungelelanise ukubonakaliswa kofuzo oluninzi, oluhlala luthe ngqo kwiintlobo ezithile zeeseli okanye izicubu; ezi proteni zinxulunyaniswa nomhlaza ezininzi xa zingahambi kakuhle, kodwa abaphandi bafumanise ukuba kunokuba nzima ukuzijolisa kuphuhliso lwamachiza kuba izinto ezikhutshelweyo zihlala ziphosakele iziza apho iimolekyuli zamachiza zidibana ngqo nazo.

I-Thalidomide kunye nezihlobo zayo zeekhemikhali i-pomalidomide kunye ne-lenalidomide inokuhlasela ngokungathanga ngqo iithagethi zabo ngokufaka iprotheni ebizwa ngokuba yi-cereblon - izinto ezimbini zokukhuphela ezine-C2H2 ZF: IKZF1 kunye ne-IKZF3. I-Cereblon yi-molecule ethile ebizwa ngokuba yi-E3 ubiquitin ligase kwaye inokuthi ibhale iiprotheyini ezithile zokuthotywa kwenkqubo ye-cellular circulatory. Ukungabikho kwe-thalidomide kunye nezihlobo zayo, i-cereblon iyayihoxisa i-IKZF1 kunye ne-IKZF3; kubukho bazo, ikhuthaza ukuqatshelwa kwezi zinto zoshicilelo kunye nokuleyibhelishwa kwazo ukuze ziqhubeke.

Indima entsha yeokuyamanduloiyeza

I-genome yomntu iyakwazi ukufaka ikhowudi malunga ne-800 yezinto ezikhutshelweyo, ezifana ne-IKZF1 kunye ne-IKZF3, ezikwazi ukunyamezela ukuguqulwa okuthile kwi-C2H2 ZF motif; ukuchonga izinto ezithile ezinokunceda kuphuhliso lwamachiza kunokunceda abaphandi bafumanise ukuba ezinye izinto ezikhutshelweyo ezifanayo zisesichengeni seziyobisi ezifana ne-thalidomide. Ukuba naliphi na ichiza elifana ne-thalidomide lalikhona, abaphandi banokumisela iipropathi ezichanekileyo ze-C2H2 ZF ezibonwa yiprotein cereblon, eyathi emva koko yavavanya amandlathalidomide, i-pomalidomide kunye ne-lenalidomide ukubangela ukuthotywa kwe-6,572 ethile ye-C2H2 ZF i-motif variants kwiimodeli zeselula. Ekugqibeleni abaphandi bachonge iiprotheni ezintandathu ezine-C2H2 ZF eziza kuba novelwano kula machiza, ezine zazo ezazingabonwa ngaphambili njengeethagethi ze-thalidomide kunye nezihlobo zayo.

Emva koko abaphandi benza ukubonakaliswa okusebenzayo kunye nesakhiwo se-IKZF1 kunye ne-IKZF3 ukuqonda ngcono iindlela zokusebenzisana phakathi kwezinto ezibhaliweyo, i-cereblon kunye ne-thalidomide yazo. Ngaphandle koko, baye baqhuba iimodeli zekhompyuter ezingama-4,661 eziguqukayo ukuze babone ukuba ezinye izinto ezikhutshelweyo zinokuqikelelwa ukuba zifakwe kwidokodo ngecereblon xa kukho ichiza. Abaphandi babonise ukuba amachiza alungiswe ngokufanelekileyo afana ne-thalidomide kufuneka akhuthaze i-cereblon ukuba ifake ithegi ye-isoforms ethile ye-C2H2 ZF transcription factor ukuze iphinde isetyenziswe.