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. Epub 2020 Jul 1.


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.

Publication types

  • Clinical Trial

MeSH terms

  • Adolescent
  • Adult
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / therapeutic use*
  • Capsid Proteins / antagonists & inhibitors*
  • Capsid Proteins / genetics
  • Capsid Proteins / metabolism
  • Cell Line
  • Cells, Cultured
  • Drug Resistance, Viral / genetics
  • Female
  • HIV-1 / drug effects*
  • HIV-1 / growth & development
  • Humans
  • Male
  • Middle Aged
  • Models, Molecular
  • Virus Replication / drug effects
  • Young Adult


  • Anti-HIV Agents
  • Capsid Proteins