Description
HIV-1 capsid inhibitor GS-6207 (lenacapavir) is a drug being developed by Gilead Sciences, Inc. It is a first-in-class, oral HIV-1 capsid inhibitor.
Uses
Lenacapavir can be useful in capsid inhibition in multidrug-resistant HIV-1 infection.
Application
Lenacapasvir was first approved in the European Union in 2022 for use in combination with other antiretroviral drugs to treat multidrug-resistant adults with HIV and those who are unable to establish a suppressive antiviral regimen. Subsequently, the drug also received similar approvals in Canada and the United States. Lenacapasvir is available as an oral and injectable therapy and is a long-acting, extended-release drug for the treatment of HIV-1. When used in combination with other antiretroviral drugs, it may only need to be administered once every 6 months, aiming to improve patient compliance and medication adherence.
Mechanism of action
Lenacapasvir works by inhibiting the HIV-1 capsid protein, a protein shell that encapsulates the viral genetic material and is involved in multiple stages of the HIV life cycle. Lenacapasvir is the first drug approved to inhibit the HIV-1 capsid, providing a new treatment option for adults with multidrug-resistant HIV infection.
Synthesis
Lenacapavir sodium (GS-6207-02) is a first-in-class HIV capsid inhibitor. Process development of the four-step final assembly of lenacapavir sodium from four synthetic intermediates was reported by Anna M. Wagner and colleagues in 2024
[1]. A bis-bromopyridine core is sequentially subjected to an alkynylation, an amide coupling with a chiral pyrazole carboxylic acid, and a Suzuki cross-coupling with an indazole boronic ester. The final step is a telescoped bis-methanesulfonylation and hydrolysis to yield the API.
References
[1] Synthesis of Lenacapavir Sodium: Active Pharmaceutical Ingredient Process Development and Scale-up. Org. Process Res. Dev. 2024, 28, 8, 3382–3395. DOI:
10.1021/acs.oprd.4c00242
