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

• 来源期刊: 中国科学:化学（英文版）
• 年，卷（期）: 2018,（11）
• 页码范围: 1430-1439
• 页数: 10页
• 语种: 英文

摘要

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 wildtype and some clinically relevant multidrug resistant HIV-1 strains.Subsequent studies on its target identification through a proteomic approach found that compound 4 might target PKM2,a rate limiting enzyme of glycolysis,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.