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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.

Author information

1
Gilead Sciences, Foster City, CA, USA. stephen.yant@gilead.com.
2
Gilead Sciences, Foster City, CA, USA.
3
Vir Biotechnology, Inc., San Francisco, CA, USA.
4
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
5
Gastroenterology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
6
Peak Gastroenterology Associates, Colorado Springs, CO, USA.
7
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.

Abstract

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.

PMID:
31501601
DOI:
10.1038/s41591-019-0560-x

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