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].

PMID: 32612233 DOI: 10.1038/s41586-020-2443-1

Abstract

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis^1-5. 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 infections^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 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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-111964

Lenacapavir

98.48%, HIV-1 Capsid Inhibitor

HIV

Infection

Name
Email *

	Sorry, but the email address you supplied was invalid.