衣壳
小分子
裂解和多聚腺苷酸化特异性因子
重组DNA
化学
生物物理学
群体特异性抗原
细胞生物学
生物
计算生物学
生物化学
聚腺苷酸
核糖核酸
基因
作者
Latesh Lad,Sheila Clancy,David Koditek,Melanie Wong,Debi Jin,Anita Niedziela‐Majka,Giuseppe A. Papalia,Magdeleine Hung,Stephen R. Yant,John R. Somoza,Eric Hu,Chien‐Hung Chou,Winston C. Tse,Randall L. Halcomb,Roman Sakowicz,Nikos Pagratis
出处
期刊:Biochemistry
[American Chemical Society]
日期:2015-03-24
卷期号:54 (13): 2240-2248
被引量:8
标识
DOI:10.1021/acs.biochem.5b00151
摘要
HIV capsid protein is an important target for antiviral drug design. High-throughput screening campaigns have identified two classes of compounds (PF74 and BI64) that directly target HIV capsid, resulting in antiviral activity against HIV-1 and HIV-2 laboratory strains. Using recombinant proteins, we developed a suite of label-free assays to mechanistically understand how these compounds modulate capsid activity. PF74 preferentially binds to the preassembled hexameric capsid form and prevents disruption of higher-order capsid structures by stabilizing capsid intersubunit interactions. BI64 binds only the monomeric capsid and locks the protein in the assembly incompetent monomeric form by disrupting capsid intersubunit interactions. We also used these assays to characterize the interaction between capsid and the host protein cleavage and polyadenylation specific factor 6 (CPSF6). Consistent with recently published results, our assays revealed CPSF6 activates capsid polymerization and preferentially binds to the preassembled hexameric capsid form similar to the small molecule compound, PF74. Furthermore, these label-free assays provide a robust method for facilitating the identification of a different class of small molecule modulators of capsid function.
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