Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins

Takuya Kobayakawa; Masaru Yokoyama; Kohei Tsuji; Masayuki Fujino; Masaki Kurakami; Takato Onishi; Sayaka Boku; Takahiro Ishii; Yutaro Miura; Kouki Shinohara; Yuki Kishihara; Nami Ohashi; Osamu Kotani; Tsutomu Murakami; Hironori Sato; Hirokazu Tamamura

doi:10.1039/D2RA06837K

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins†

Takuya Kobayakawa,

^a Masaru Yokoyama,^b Kohei Tsuji,

^a Masayuki Fujino,^c Masaki Kurakami,^a Takato Onishi,^a Sayaka Boku,^a Takahiro Ishii,^a Yutaro Miura,^a Kouki Shinohara,^a Yuki Kishihara,^a Nami Ohashi,^d Osamu Kotani,^b Tsutomu Murakami,*^c Hironori Sato*^b and Hirokazu Tamamura

*^a

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* Corresponding authors

^a Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
E-mail: tamamura.mr@tmd.ac.jp

^b Pathogen Genomics Center, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, Japan
E-mail: hirosato@nih.go.jp

^c AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan
E-mail: tmura@nih.go.jp

^d Showa Pharmaceutical University, Machida 194-8543, Tokyo, Japan

Abstract

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 in silico 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.

RSC Advances

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins†

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Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins

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