Mankhwalathalidomideidakumbukiridwa mu 1960s chifukwa idayambitsa zolakwika zowopsa kwa ana obadwa kumene, koma nthawi yomweyo idagwiritsidwa ntchito kwambiri pochiza multiple sclerosis ndi khansa zina zamagazi, ndipo imatha, ndi achibale ake amankhwala, kulimbikitsa kuwonongeka kwa ma cell a mapuloteni awiri enieni omwe ali mamembala a banja la mapuloteni okhazikika "opanda mankhwala" (zolemba zolemba) zomwe zimakhala ndi mamolekyu apadera, C2H2 zinc finger motif.

Mu kafukufuku waposachedwapa wofalitsidwa mu magazini yapadziko lonse ya Science, asayansi ochokera ku MIT Boulder Institute ndi mabungwe ena anapeza kuti thalidomide ndi mankhwala okhudzana nawo angapereke poyambira kuti ochita kafukufuku apange mtundu watsopano wa mankhwala oletsa khansa omwe akuyembekezeka kutsata pafupifupi 800. zolembera zomwe zimagawana malingaliro omwewo. Zinthu zolembera zimamangiriza ku DNA ndikugwirizanitsa mafotokozedwe a majini angapo, omwe nthawi zambiri amakhala achindunji ku mitundu ina ya maselo kapena minyewa; Mapuloteniwa amagwirizanitsidwa ndi khansa zambiri zikamayenda molakwika, koma ofufuza apeza kuti zingakhale zovuta kuwatsata kuti apange mankhwala osokoneza bongo chifukwa zinthu zolembera nthawi zambiri zimaphonya malo omwe mamolekyu a mankhwala amakumana nawo mwachindunji.

Thalidomide ndi mankhwala achibale ake pomalidomide ndi lenalidomide akhoza kuwononga zolinga zawo mosalunjika polemba puloteni yotchedwa cereblon - zinthu ziwiri zolembera zomwe zili ndi C2H2 ZF: IKZF1 ndi IKZF3. Cereblon ndi molekyulu yeniyeni yotchedwa E3 ubiquitin ligase ndipo imatha kutchula mapuloteni enieni kuti awonongeke ndi kayendedwe ka ma cellular. Popanda thalidomide ndi achibale ake, cereblon imanyalanyaza IKZF1 ndi IKZF3; pamaso pawo, zimalimbikitsa kuzindikira zinthu zolembedwazi ndi zilembo zake kuti zikonzedwe.

Ntchito yatsopano yaizizakalemankhwala

Genome ya munthu imatha kusindikiza zinthu pafupifupi 800, monga IKZF1 ndi IKZF3, zomwe zimatha kulekerera masinthidwe ena mu C2H2 ZF motif; kuzindikira zinthu zenizeni zomwe zingathandize pakupanga mankhwala kungathandize ofufuza kudziwa ngati zinthu zina zofananira zojambulidwa zimatha kutenga mankhwala ngati thalidomide. Ngati mankhwala aliwonse amtundu wa thalidomide analipo, ofufuzawo amatha kudziwa zenizeni za C2H2 ZF zomwe zimawonedwa ndi protein cereblon, yomwe idawunikiranso mphamvu yathalidomide, pomalidomide ndi lenalidomide kuti apangitse kuwonongeka kwa 6,572 yeniyeni ya C2H2 ZF mitundu yosiyanasiyana yamitundu yama cellular. Potsirizira pake ofufuzawo adapeza mapuloteni asanu ndi limodzi a C2H2 ZF omwe angakhale okhudzidwa ndi mankhwalawa, anayi omwe sanaganizidwe kuti ndi zolinga za thalidomide ndi achibale ake.

Kenako ofufuzawo adachita mawonekedwe owoneka bwino a IKZF1 ndi IKZF3 kuti amvetsetse bwino njira zolumikizirana pakati pa zinthu zolembera, cereblon ndi thalidomide yawo. Kupatula apo, adayendetsanso mitundu 4,661 yamakompyuta osinthika kuti awone ngati zinthu zina zolembedwa zitha kuneneratu kuti zitha kukhala ndi cereblon pamaso pa mankhwalawa. Ofufuzawo adawonetsa kuti mankhwala osinthidwa moyenera ngati thalidomide amayenera kukopa cereblon kuti alembe ma isoforms a C2H2 ZF transcript factor kuti agwiritsenso ntchito.