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Clinical targeting of HIV capsid protein with a long-acting small molecule

John O. Link, Martin S. Rhee, Winston C. Tse, Jim Zheng, John R. Somoza, William Rowe, Rebecca Begley, Anna Chiu, Andrew Mulato, Derek Hansen, Eric Singer, Luong K. Tsai, Rujuta A. Bam, Chien-Hung Chou, Eda Canales, Gediminas Brizgys, Jennifer R. Zhang, Jiayao Li, Michael Graupe, Philip Morganelli, Qi Liu, Qiaoyin Wu, Randall L. Halcomb, Roland D. Saito, Scott D. Schroeder, Scott E. Lazerwith, Steven Bondy, Debi Jin, Magdeleine Hung, Nikolai Novikov, Xiaohong Liu, Armando G. Villaseñor, Carina E. Cannizzaro, Eric Y. Hu, Robert L. Anderson, Todd C. Appleby, Bing Lu, Judy Mwangi, Albert Liclican, Anita Niedziela-Majka, Giuseppe A. Papalia, Melanie H. Wong, Stephanie A. Leavitt, Yili Xu, David Koditek, George J. Stepan, Helen Yu, Nikos Pagratis, Sheila Clancy, Shekeba Ahmadyar, Terrence Z. Cai, Scott Sellers, Scott A. Wolckenhauer, John Ling, Christian Callebaut, Nicolas Margot, Renee R. Ram, Ya-Pei Liu, Rob Hyland, Gary I. Sinclair, Peter J. Ruane, Gordon E. Crofoot, Cheryl K. McDonald, Diana M. Brainard, Latesh Lad, Swami Swaminathan, Wesley I. Sundquist, Roman Sakowicz, Anne E. Chester, William E. Lee, Eric S. Daar, Stephen R. Yant () and Tomas Cihlar
Additional contact information
John O. Link: Gilead Sciences
Martin S. Rhee: Gilead Sciences
Winston C. Tse: Gilead Sciences
Jim Zheng: Gilead Sciences
John R. Somoza: Gilead Sciences
William Rowe: Gilead Sciences
Rebecca Begley: Gilead Sciences
Anna Chiu: Gilead Sciences
Andrew Mulato: Gilead Sciences
Derek Hansen: Gilead Sciences
Eric Singer: Gilead Sciences
Luong K. Tsai: Gilead Sciences
Rujuta A. Bam: Gilead Sciences
Chien-Hung Chou: Gilead Sciences
Eda Canales: Gilead Sciences
Gediminas Brizgys: Gilead Sciences
Jennifer R. Zhang: Gilead Sciences
Jiayao Li: Gilead Sciences
Michael Graupe: Gilead Sciences
Philip Morganelli: Gilead Sciences
Qi Liu: Gilead Sciences
Qiaoyin Wu: Gilead Sciences
Randall L. Halcomb: Gilead Sciences
Roland D. Saito: Gilead Sciences
Scott D. Schroeder: Gilead Sciences
Scott E. Lazerwith: Gilead Sciences
Steven Bondy: Gilead Sciences
Debi Jin: Gilead Sciences
Magdeleine Hung: Gilead Sciences
Nikolai Novikov: Gilead Sciences
Xiaohong Liu: Gilead Sciences
Armando G. Villaseñor: Gilead Sciences
Carina E. Cannizzaro: Gilead Sciences
Eric Y. Hu: Gilead Sciences
Robert L. Anderson: Gilead Sciences
Todd C. Appleby: Gilead Sciences
Bing Lu: Gilead Sciences
Judy Mwangi: Gilead Sciences
Albert Liclican: Gilead Sciences
Anita Niedziela-Majka: Gilead Sciences
Giuseppe A. Papalia: Gilead Sciences
Melanie H. Wong: Gilead Sciences
Stephanie A. Leavitt: Gilead Sciences
Yili Xu: Gilead Sciences
David Koditek: Gilead Sciences
George J. Stepan: Gilead Sciences
Helen Yu: Gilead Sciences
Nikos Pagratis: Gilead Sciences
Sheila Clancy: Gilead Sciences
Shekeba Ahmadyar: Gilead Sciences
Terrence Z. Cai: Gilead Sciences
Scott Sellers: Gilead Sciences
Scott A. Wolckenhauer: Gilead Sciences
John Ling: Gilead Sciences
Christian Callebaut: Gilead Sciences
Nicolas Margot: Gilead Sciences
Renee R. Ram: Gilead Sciences
Ya-Pei Liu: Gilead Sciences
Rob Hyland: Gilead Sciences
Gary I. Sinclair: AIDS Arms Inc, DBA Prism Health North Texas
Peter J. Ruane: Ruane Clinical Research Group Inc
Gordon E. Crofoot: The Crofoot Research Center Inc
Cheryl K. McDonald: Texas Centers for Infectious Disease Associates
Diana M. Brainard: Gilead Sciences
Latesh Lad: Gilead Sciences
Swami Swaminathan: Gilead Sciences
Wesley I. Sundquist: University of Utah School of Medicine
Roman Sakowicz: Gilead Sciences
Anne E. Chester: Gilead Sciences
William E. Lee: Gilead Sciences
Eric S. Daar: David Geffen School of Medicine at UCLA
Stephen R. Yant: Gilead Sciences
Tomas Cihlar: Gilead Sciences

Nature, 2020, vol. 584, issue 7822, 614-618

Abstract: 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.

Date: 2020
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Citations: View citations in EconPapers (2)

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DOI: 10.1038/s41586-020-2443-1

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