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Nat Med. 2019 Sep;25(9):1377-1384. doi: 10.1038/s41591-019-0560-x. Epub 2019 Sep 9.

A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model.

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Gilead Sciences, Foster City, CA, USA.
Gilead Sciences, Foster City, CA, USA.
Vir Biotechnology, Inc., San Francisco, CA, USA.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Gastroenterology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Peak Gastroenterology Associates, Colorado Springs, CO, USA.
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.


People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1-3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.


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