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A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model. 2019
Stephen R Yant, and
Andrew Mulato, and
Derek Hansen, and
Winston C Tse, and
Anita Niedziela-Majka, and
Jennifer R Zhang, and
George J Stepan, and
Debi Jin, and
Melanie H Wong, and
Jill M Perreira, and
Eric Singer, and
Giuseppe A Papalia, and
Eric Y Hu, and
Jim Zheng, and
Bing Lu, and
Scott D Schroeder, and
Kevin Chou, and
Shekeba Ahmadyar, and
Albert Liclican, and
Helen Yu, and
Nikolai Novikov, and
Eric Paoli, and
Daniel Gonik, and
Renee R Ram, and
Magdeleine Hung, and
William M McDougall, and
Abraham L Brass, and
Wesley I Sundquist, and
Tomas Cihlar, and
John O Link
Gilead Sciences, Foster City, CA, USA. stephen.yant@gilead.com.
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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