Nature medicine · 2019
A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Yant Stephen R, Mulato Andrew, Hansen Derek, Tse Winston C, Niedziela-Majka Anita, Zhang Jennifer R, Stepan George J, Jin Debi, Wong Melanie H, Perreira Jill M, Singer Eric, Papalia Giuseppe A, Hu Eric Y, Zheng Jim, Lu Bing, Schroeder Scott D, Chou Kevin, Ahmadyar Shekeba, Liclican Albert, Yu Helen, Novikov Nikolai, Paoli Eric, Gonik Daniel, Ram Renee R, Hung Magdeleine, McDougall William M, Brass Abraham L, Sundquist Wesley I, Cihlar Tomas, Link John O
Аннотация
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.