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Chapter 18 - Lenacapavir: a first-in-class HIV-1 capsid inhibitor for the treatment of multidrug-resistant HIV infections
Book chapter

Chapter 18 - Lenacapavir: a first-in-class HIV-1 capsid inhibitor for the treatment of multidrug-resistant HIV infections

Dang Ding, Dazhou Shi, Shujing Xu, Yang Zhou, Xiangyi Jiang, Xinyong Liu, Alexej Dick and Peng Zhan
Drug Discovery Stories, pp 341-349
2025

Abstract

capsid drug design HIV-1 Lenacapavir
Combination antiretroviral therapy (cART) has provided exceptional advancements in the management of HIV, significantly reducing morbidity and mortality. However, the onset of multidrug-resistant strains and the long-term toxicity of current medications underscore the urgent need for new antiretroviral drugs with novel mechanisms. The HIV-1 capsid (CA) protein is a prime therapeutic target owing to its pivotal role in the virus’s life cycle and its high degree of conservation across different HIV-1 strains. The interprotomer pocket between the N-terminal domain (NTD) and the C-terminal domain (CTD) within the CA protein serves as a crucial interaction site for host dependency factors, as well as for the innovative small-molecule modulator Lenacapavir (LEN). LEN, distinguished by its potent antiviral efficacy and long-acting nature, is the first drug approved to target the HIV-1 CA protein. This chapter provides an overview of the discovery of LEN, elucidates its mechanism of action, and discusses the clinical trials that led to its groundbreaking advent in antiretroviral drug development.

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