Kobayakawa Takuya, Yokoyama Masaru, Tsuji Kohei, Fujino Masayuki, Kurakami Masaki, Onishi Takato, Boku Sayaka, Ishii Takahiro, Miura Yutaro, Shinohara Kouki, Kishihara Yuki, Ohashi Nami, Kotani Osamu, Murakami Tsutomu, Sato Hironori, Tamamura Hirokazu
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) 2-3-10 Kandasurugadai, Chiyoda-ku Tokyo 101-0062 Japan
Pathogen Genomics Center, National Institute of Infectious Diseases Musashimurayama 208-0011 Tokyo Japan
RSC Adv. 2023 Jan 12;13(3):2156-2167. doi: 10.1039/d2ra06837k. eCollection 2023 Jan 6.
The HIV-1 capsid is a shell that encapsulates viral RNA, and forms a conical structure by assembling oligomers of capsid (CA) proteins. Since the CA proteins are highly conserved among many strains of HIV-1, the inhibition of the CA function could be an appropriate goal for suppression of HIV-1 replication, but to date, no drug targeting CA has been developed. Hydrophobic interactions between two CA molecules through Trp184 and Met185 in the protein are known to be indispensable for conformational stabilization of the CA multimer. In our previous study, a small molecule designed by screening as a dipeptide mimic of Trp184 and Met185 in the interaction site was synthesized and found to have significant anti-HIV-1 activity. In the present study, molecules with different scaffolds based on a dipeptide mimic of Trp184 and Met185 have been designed and synthesized. Their significant anti-HIV activity and their advantages compared to the previous compounds were examined. The present results should be useful in the design of novel CA-targeting anti-HIV agents.
人类免疫缺陷病毒1型（HIV-1）衣壳是一种包裹病毒RNA的外壳，通过组装衣壳（CA）蛋白的寡聚体形成锥形结构。由于CA蛋白在许多HIV-1毒株中高度保守，抑制CA功能可能是抑制HIV-1复制的一个合适目标，但迄今为止，尚未开发出靶向CA的药物。已知蛋白质中两个CA分子通过色氨酸184（Trp184）和甲硫氨酸185（Met185）之间的疏水相互作用对于CA多聚体的构象稳定是必不可少的。在我们之前的研究中，通过筛选设计了一种小分子，作为相互作用位点中Trp184和Met185的二肽模拟物进行合成，发现其具有显著的抗HIV-1活性。在本研究中，基于Trp184和Met185的二肽模拟物设计并合成了具有不同骨架的分子。研究了它们显著的抗HIV活性以及与先前化合物相比的优势。目前的结果应有助于新型CA靶向抗HIV药物的设计。
