Sawyer Aubrey M, Vaca Cristina C, Malik Neha, Clerc Isabelle, Craft Joshua, Hudson Hannah, Scholtés Gaël K, Schiltz Gary E, Roh Meejeon, Song Chisu, D'Aquila Richard T
Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Chemistry, Northwestern University Weinberg College of Arts and Sciences, Evanston, IL 60208, USA.
Viruses. 2025 Apr 1;17(4):514. doi: 10.3390/v17040514.
The cytoplasmic human Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) cytidine deaminases G and F (A3G and A3F) can block the spread of human immunodeficiency virus (HIV). HIV counteracts this cell-intrinsic defense through a viral protein called viral infectivity factor (Vif). Vif causes proteasomal degradation of A3G and A3F proteins (A3G/F) in HIV-producing cells to ensure infectivity of virions subsequently released from these cells. Here, we optimized a lead compound reported previously to boost cellular levels of A3G. The modified analogs designed, synthesized, and evaluated here inhibit cell-mediated post-translational degradation of A3G/F, whether Vif is present or not. This increases A3G/F incorporation into Vif-positive virions to decrease viral infectivity. The compounds and processes described here can facilitate the development of new anti-HIV therapeutics whose host-targeted effect may not be evaded by resistance-conferring mutations in HIV Vif.
细胞质中的人类载脂蛋白B信使核糖核酸编辑酶催化多肽样3（APOBEC3或A3）胞苷脱氨酶G和F（A3G和A3F）可阻断人类免疫缺陷病毒（HIV）的传播。HIV通过一种名为病毒感染因子（Vif）的病毒蛋白来对抗这种细胞内在防御。Vif导致HIV产生细胞中A3G和A3F蛋白（A3G/F）的蛋白酶体降解，以确保随后从这些细胞释放的病毒粒子具有感染性。在此，我们优化了先前报道的一种先导化合物，以提高细胞内A3G的水平。本文设计、合成并评估的修饰类似物可抑制细胞介导的A3G/F翻译后降解，无论是否存在Vif。这增加了A3G/F掺入Vif阳性病毒粒子中，从而降低病毒感染性。本文所述的化合物和方法可促进新型抗HIV疗法的开发，HIV Vif中赋予耐药性的突变可能无法规避其针对宿主的效应。
