A heterocyclic compound inhibits viral release by inducing cell surface BST2/Tetherin/CD317/HM1.24

• Published in: The Journal of biological chemistry 2024-09, Vol.300 (9), p.107701, Article 107701
• Main Authors: Nyame, Perpetual, Togami, Akihiro, Yoshida, Tomofumi, Masunaga, Takuya, Begum, MST Monira, Terasawa, Hiromi, Monde, Nami, Tahara, Yurika, Tanaka, Reiko, Tanaka, Yuetsu, Appiah-Kubi, Joyce, Amesimeku, Wright Andrews Ofotsu, Hossain, Md Jakir, Otsuka, Masami, Yoshimura, Kazuhisa, Ikeda, Terumasa, Sawa, Tomohiro, Satou, Yorifumi, Fujita, Mikako, Maeda, Yosuke, Tateishi, Hiroshi, Monde, Kazuaki
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - pharmacology; Antigens, CD - genetics; Antigens, CD - metabolism; Bone Marrow Stromal Antigen 2; BST2; drug screening; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Heterocyclic Compounds - pharmacology; HIV Infections - drug therapy; HIV Infections - metabolism; HIV Infections - virology; HIV-1; HIV-1 - drug effects; Humans; Jurkat Cells; SARS-CoV-2; SARS-CoV-2 - drug effects; SARS-CoV-2 - metabolism; Simian Immunodeficiency Virus - drug effects; SIVmac239; tetherin; Virus Release - drug effects; Vpu
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2024.107701

The introduction of combined antiretroviral therapy (cART) has greatly improved the quality of life of human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, the ever-present desire to seek out a full remedy for HIV-1 infections makes the discovery of novel antiviral medication compelling. Owing to this, a new late-stage inhibitor, Lenacapavir/Sunlenca, an HIV multi-phase suppressor, was clinically authorized in 2022. Besides unveiling cutting-edge antivirals inhibiting late-stage proteins or processes, newer therapeutics targeting host restriction factors hold promise for the curative care of HIV-1 infections. Notwithstanding, bone marrow stromal antigen 2 (BST2)/Tetherin/CD317/HM1.24, which entraps progeny virions is an appealing HIV-1 therapeutic candidate. In this study, a novel drug screening system was established, using the Jurkat/Vpr-HiBiT T cells, to identify drugs that could obstruct HIV-1 release; the candidate compounds were selected from the Ono Pharmaceutical compound library. Jurkat T cells expressing Vpr-HiBiT were infected with NL4-3, and the amount of virus release was quantified indirectly by the amount of Vpr-HiBiT incorporated into the progeny virions. Subsequently, the candidate compounds that suppressed viral release were used to synthesize the heterocyclic compound, HT-7, which reduces HIV-1 release with less cellular toxicity. Notably, HT-7 increased cell surface BST2 coupled with HIV-1 release reduction in Jurkat cells but not Jurkat/KO-BST2 cells. Seemingly, HT-7 impeded simian immunodeficiency virus (SIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) release. Concisely, these results suggest that the reduction in viral release, following HT-7 treatment, resulted from the modulation of cell surface expression of BST2 by HT-7.