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Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis.sup.1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance.sup.6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment--which contributes to virologic failure, resistance generation and viral transmission--as well as of pre-exposure prophylaxis, leading to new infections.sup.1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence.sup.10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log.sub.10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection., Author(s): John O. Link [sup.1] , Martin S. Rhee [sup.1] , Winston C. Tse [sup.1] [sup.8] , Jim Zheng [sup.1] , John R. Somoza [sup.1] , William Rowe [sup.1] , [...]

Author(s): Robert N. Kirchdoerfer [1]; Christopher A. Cottrell [1]; Nianshuang Wang [2]; Jesper Pallesen [1]; Hadi M. Yassine [3]; Hannah L. Turner [1]; Kizzmekia S. Corbett [3]; Barney S. Graham [...]

Author(s): Gabriel L. Butterfield [1, 2, 3]; Marc J. Lajoie [1, 2]; Heather H. Gustafson [4, 5]; Drew L. Sellers [4, 5, 6]; Una Nattermann [1, 2, 7]; Daniel Ellis [...]