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A new class of HIV-1 inhibitors and the target identification via proteomic profiling

Science China Chemistry 2018年第11期61卷 1430-1439页

作者： Ying-Zi Ge Bin Zhou Ruo-Xuan Xiao Xiao-Jing Yuan Hu Zhou Ye-Chun Xu Mark A.Wainberg Ying-Shan Han Jian-Min Yue State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences McGill University AIDS Centre Lady Davis Institute for Medical Research Jewish General Hospital

Anti-HIV screening with the MT-4/MTT assay on a focused library of structurally diverse natural products has led to the discovery of a group of steroids with potent activities, which include four new ergostane-type steroids, named amotsterols A-D （1-4）, together with two known analogs. Among them, the most potent amotsterol D （4） exhibited anti-HIV activity against wild- type and some clinically relevant multidrug resistant HIV-I strains. Subsequent studies on its target identification through a proteomic approach found that compound 4 might target PKM2, a rate limiting enzyme ofglycolysis, in host cells to restrict HIV replication. The docking model of compound 4 to PKM2 showed that the two hydroxyl groups of 4 form hydrogen bonds with the two parallel Y390 in each subunit of PKM2 separately, and the ring C of 4 is sandwiched between the two parallel aromatic rings ofF26. The identified hit compound may have the potential to be further developed as a novel anti-HIVagent. These results demonstrated that an integrated approach, which combines new chemical structures and phenotypic screening with a proteomic approach, could not only identify novel HIV-1 inhibitors, but also elucidate the unknown targets of compound interactions in antiviral drug discovery.

关键词： ergostane-type steroids anti-HIV target identification PKM2

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