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首页> 外文期刊>Antimicrobial agents and chemotherapy. >New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
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New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.

机译：针对人类免疫缺陷病毒1型病毒粒子成熟的新型小分子抑制剂。

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A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
机译：从人类免疫缺陷病毒1型（HIV-1）抗病毒筛选中鉴定出了一种新型的靶向病毒粒子成熟的小分子抑制剂。 PF-46396是一种代表性分子，在T细胞系和外周血单核细胞（PBMC）中表现出针对HIV-1实验室菌株和临床分离株的抗病毒活性。 PF-46396特异性抑制衣壳（CA）/间隔肽1（SP1）（p25）的加工，导致CA / SP1（p25）前体蛋白积聚并阻止了病毒核心颗粒的成熟。抵抗PF-46396的病毒变体在HIV-1 CA序列（CAI201V）中包含一个氨基酸取代，位于一级结构中CA / SP1裂解位点的远端，我们证明这足以赋予对PF-46396和3-O-（3'，3'-二甲基琥珀酰基）桦木酸（DSB），先前描述的成熟抑制剂。相反，以前与DSB体外抗性相关的SP1（SP1A1V）中的单个氨基取代足以赋予对DSB和PF-46396的抗性。此外，在用PF-46396或DSB处理过的HIV-1感染的细胞中，CAI201V替代恢复了CA / SP1的加工。我们的研究结果表明，PF-46396通过类似于DSB的机制来抑制HIV-1病毒粒子的成熟。据我们所知，PF-46396代表第一种小分子HIV-1成熟抑制剂，其化学类别与源自白桦酸的成熟抑制剂（例如DSB）不同，证明了不同化学类别的分子可以抑制这种机制。

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