Department of Chemistry, 361 Roger Adams Laboratory, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
J Med Chem. 2012 May 10;55(9):4132-41. doi: 10.1021/jm2007694. Epub 2012 May 1.
Stem-loop 3 RNA (SL3) in ψ-RNA is a highly conserved motif in different strains of HIV-1 and serves as a principle determinant for viral packaging. Viral encapsulation is critical for viral replication, and disruption of the nucleocapsid-ψ-RNA complex interferes with viral replication. We have used SL3 RNA as a target for identification of small molecule inhibitors of the interactions of nucleocapsid protein (NCp7) and ψ-RNA. We report the use of computational and high-throughput screening approaches to identify 16 compounds that bind SL3 RNA with micromolar affinities. Among the identified ligands, two molecules, compounds 7 and 17, bind with higher affinity to SL3 RNA than to double- and single-stranded RNAs. Four of the 16 SL3 RNA ligands inhibit interactions between SL3 RNA and NCp7 with micromolar inhibition constants. In general, the identified SL3 ligands have simple molecular structures and low molecular weights and are, therefore, possible lead compounds for the development of ligands that target the elements of ψ-RNA of HIV-1 with high affinity and specificity.
ψ-RNA 中的茎环 3 RNA (SL3) 是 HIV-1 不同株系中高度保守的基序，是病毒包装的主要决定因素。病毒包封对于病毒复制至关重要，核衣壳-ψ-RNA 复合物的破坏会干扰病毒复制。我们已将 SL3 RNA 用作鉴定核衣壳蛋白 (NCp7) 和 ψ-RNA 相互作用的小分子抑制剂的靶标。我们报告了使用计算和高通量筛选方法来鉴定 16 种与微摩尔亲和力结合 SL3 RNA 的化合物。在所鉴定的配体中，两种分子化合物 7 和 17 与 SL3 RNA 的结合亲和力高于双链和单链 RNA。在 16 种 SL3 RNA 配体中，有 4 种以微摩尔抑制常数抑制 SL3 RNA 与 NCp7 之间的相互作用。总的来说，所鉴定的 SL3 配体具有简单的分子结构和低分子量，因此可能是开发高亲和力和特异性靶向 HIV-1 ψ-RNA 元件的配体的先导化合物。
