Inhibitors of HIV-1 Attachment

About the Talk

Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. An indole-3-glyoxamide derivative was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir, which exhibited an improved antiviral and pharmacokinetic profile compared to prototype compounds and has completed phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir, a prodrug designed to address dissolution- and solubility-limited absorption issues. In this presentation, we will summarize the structure−activity and structure−liability studies leading to the discovery of temsavir and the clinical studies that entailed the development of an extended release formulation suitable for further development. Fostemsavir was approved for clinical use by the FDA in July 2020 and by the EMA in February, 2021 and is marketed as Rukobia.

About Speaker

Nicholas A. Meanwell joined Bristol Myers Squibb in 1982 and retired in 2022 after having led drug discovery programs in the cardiovascular, neurosciences and virology therapeutic areas, work that resulted in the advancement of 33 clinical candidates. Nick and his team were involved in the design and development of flindokalner (MaxiPost®) (P3 for the treatment of stroke), the HIV-1 attachment inhibitor fostemsavir (RukobiaTM), the HIV-1 maturation inhibitors BMS-955176, GSK3640254 (fipravirimat) and VH3739937 (zegruvirimat), the HCV NS5A inhibitor daclatasvir (DaklinzaTM), the HCV NS3 protease inhibitors BMS-605339 and asunaprevir (SunvepraTM), and the HCV NS5B inhibitor beclabuvir, marketed as XymencyTM, a fixed dose combination with daclatasvir and asunaprevir.

Nick has authored/co-authored more than 300 publications, review articles, book chapters and editorials and 210 meeting abstracts and presented more than 250 invited lectures at National and International meetings, Universities and Schools on Medicinal Chemistry. He is named as an inventor/co-inventor of 145 issued U.S. Patents. Nick has organized/co-organized

more than 75 sessions at National and International Meetings, ACS Webinars in Drug Discovery, ACS Prospectives Meetings and Short Courses on aspects of drug design. He was Associate Editor for the Journal of Medicinal Chemistry with responsibility for Perspectives articles 2017-2023.

Nick was the recipient of the 2015 Philip S. Portoghese Medicinal Chemistry Lectureship Award administered jointly by the ACS Division of Medicinal Chemistry and the Journal of Medicinal Chemistry. He was inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2015, was the co-recipient of “Heroes of Chemistry” Awards sponsored by the

American Chemical Society in 2017 and 2023 and was the recipient of the 2022 Alfred Burger Award in Medicinal Chemistry sponsored by the American Chemical Society. He was appointed a Fellow of the American Chemical Society in August 2022, was named as the recipient of the 2024 Antonín Holý Memorial Award administered by the International Society for Antiviral Research and recipient of the 2025 Scientific Achievement in Drug Discovery and Development Award administered by the American Society for Pharmacology and Experimental Therapeutics (ASPET).

Nick received his Ph.D. degree from the University of Sheffield under the supervision of Dr. D. Neville Jones and competed a post-doctoral fellowship with Professor Carl R. Johnson at Wayne State University