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.
John O Link  1 ,  Martin S Rhee  1 ,  Winston C Tse  1  2 ,  Jim Zheng  1 ,  John R Somoza  1 ,  William Rowe  1 ,  Rebecca Begley  1 ,  Anna Chiu  1 ,  Andrew Mulato  1 ,  Derek Hansen  1 ,  Eric Singer  1 ,  Luong K Tsai  1 ,  Rujuta A Bam  1 ,  Chien-Hung Chou  1 ,  Eda Canales  1 ,  Gediminas Brizgys  1 ,  Jennifer R Zhang  1 ,  Jiayao Li  1 ,  Michael Graupe  1 ,  Philip Morganelli  1 ,  Qi Liu  1  3 ,  Qiaoyin Wu  1 ,  Randall L Halcomb  1  4 ,  Roland D Saito  1  2 ,  Scott D Schroeder  1 ,  Scott E Lazerwith  1 ,  Steven Bondy  1 ,  Debi Jin  1 ,  Magdeleine Hung  1 ,  Nikolai Novikov  1 ,  Xiaohong Liu  1 ,  Armando G Villaseñor  1 ,  Carina E Cannizzaro  1 ,  Eric Y Hu  1 ,  Robert L Anderson  1  5 ,  Todd C Appleby  1 ,  Bing Lu  1 ,  Judy Mwangi  1 ,  Albert Liclican  1 ,  Anita Niedziela-Majka  1 ,  Giuseppe A Papalia  1 ,  Melanie H Wong  1 ,  Stephanie A Leavitt  1 ,  Yili Xu  1 ,  David Koditek  1 ,  George J Stepan  1 ,  Helen Yu  1 ,  Nikos Pagratis  1 ,  Sheila Clancy  1 ,  Shekeba Ahmadyar  1 ,  Terrence Z Cai  1  6 ,  Scott Sellers  1 ,  Scott A Wolckenhauer  1 ,  John Ling  1 ,  Christian Callebaut  1 ,  Nicolas Margot  1 ,  Renee R Ram  1 ,  Ya-Pei Liu  1 ,  Rob Hyland  1 ,  Gary I Sinclair  7 ,  Peter J Ruane  8 ,  Gordon E Crofoot  9 ,  Cheryl K McDonald  10 ,  Diana M Brainard  1 ,  Latesh Lad  1 ,  Swami Swaminathan  1 ,  Wesley I Sundquist  11 ,  Roman Sakowicz  1 ,  Anne E Chester  1 ,  William E Lee  1 ,  Eric S Daar  12 ,  Stephen R Yant  13 ,  Tomas Cihlar  1
Affiliations
  • 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].
Abstract

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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