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

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.

• Authors: Stephen R Yant, Andrew Mulato, Derek Hansen, Winston C Tse, Anita Niedziela-Majka, Jennifer R Zhang, George J Stepan, Debi Jin, Melanie H Wong, Jill M Perreira, Eric Singer, Giuseppe A Papalia, Eric Y Hu, Jim Zheng, Bing Lu, Scott D Schroeder, Kevin Chou, Shekeba Ahmadyar, Albert Liclican, Helen Yu, Nikolai Novikov, Eric Paoli, Daniel Gonik, Renee R Ram, Magdeleine Hung, William M McDougall, Abraham L Brass, Wesley I Sundquist, Tomas Cihlar, John O Link
• Journal: Nature medicine (Nat Med) Vol. 25 Issue 9 Pg. 1377-1384 (09 2019) ISSN: 1546-170X [Electronic] United States
• PMID: 31501601 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Capsid Proteins
• DNA, Viral
• Delayed-Action Preparations
• GS-CA1
• Indazoles
• Pyridines
• Small Molecule Libraries

Topics

• Animals
• Anti-HIV Agents (pharmacology, therapeutic use)
• Capsid (drug effects, metabolism)
• Capsid Proteins (antagonists & inhibitors, genetics)
• DNA, Viral (drug effects)
• Delayed-Action Preparations
• Drug Resistance, Viral (drug effects)
• HIV Infections (drug therapy, genetics, virology)
• HIV-1 (drug effects, genetics, pathogenicity)
• HIV-2 (drug effects, pathogenicity)
• Humans
• Indazoles (pharmacology, therapeutic use)
• Medication Adherence
• Mice
• Pyridines (pharmacology, therapeutic use)
• Small Molecule Libraries (pharmacology)