학술논문
A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model
Document Type
Original Paper
Author
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.
Source
Nature Medicine. 25(9):1377-1384
Subject
Language
English
ISSN
1078-8956
1546-170X
1546-170X
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.
A new compound that inhibits HIV capsid assembly and nuclear transport functions offers potential as a long-acting antiretroviral.
A new compound that inhibits HIV capsid assembly and nuclear transport functions offers potential as a long-acting antiretroviral.