化学
磷酸核糖转移酶
前药
生物化学
次黄嘌呤
核苷
酶
活动站点
嘌呤
黄嘌呤
鸟嘌呤
立体化学
次黄嘌呤鸟嘌呤磷酸核糖转移酶
核苷酸
突变体
基因
作者
Dianne T. Keough,Magdalena Petrová,G. J. King,Michal Kratochvíl,Michal Kratochvíl,Radek Pohl,Eva Doleželová,Alena Zı́ková,L.W. Guddat,Dominik Rejman
标识
DOI:10.1021/acs.jmedchem.4c00021
摘要
Inhibition of hypoxanthine–guanine–xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have Ki values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against TBr in cell culture, a prodrug exhibited an EC50 of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents.
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