Clinical targeting of HIV capsid protein with a long-acting small molecule
- Nature. 2020 Aug;584(7822):614-618. doi: 10.1038/s41586-020-2443-1.
- 1. Gilead Sciences, Foster City, CA, USA.
- 2. Vir Biotechnology Inc, San Francisco, CA, USA.
- 3. Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
- 4. Terns Pharmaceuticals, Foster City, CA, USA.
- 5. MyoKardia Inc, South San Francisco, CA, USA.
- 6. Bayer, Berkeley, CA, USA.
- 7. AIDS Arms Inc, DBA Prism Health North Texas, Dallas, TX, USA.
- 8. Ruane Clinical Research Group Inc, Los Angeles, CA, USA.
- 9. The Crofoot Research Center Inc, Houston, TX, USA.
- 10. Texas Centers for Infectious Disease Associates, Fort Worth, TX, USA.
- 11. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.
- 12. Division of HIV Medicine at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Torrance, CA, USA.
- 13. Gilead Sciences, Foster City, CA, USA. [email protected].
Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. 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 infections1,2,4,7-9. 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 adherence10. 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 log10-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.
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