| Literature DB >> 32612233 |
John O Link1, Martin S Rhee1, Winston C Tse1,2, Jim Zheng1, John R Somoza1, William Rowe1, Rebecca Begley1, Anna Chiu1, Andrew Mulato1, Derek Hansen1, Eric Singer1, Luong K Tsai1, Rujuta A Bam1, Chien-Hung Chou1, Eda Canales1, Gediminas Brizgys1, Jennifer R Zhang1, Jiayao Li1, Michael Graupe1, Philip Morganelli1, Qi Liu1,3, Qiaoyin Wu1, Randall L Halcomb1,4, Roland D Saito1,2, Scott D Schroeder1, Scott E Lazerwith1, Steven Bondy1, Debi Jin1, Magdeleine Hung1, Nikolai Novikov1, Xiaohong Liu1, Armando G Villaseñor1, Carina E Cannizzaro1, Eric Y Hu1, Robert L Anderson1,5, Todd C Appleby1, Bing Lu1, Judy Mwangi1, Albert Liclican1, Anita Niedziela-Majka1, Giuseppe A Papalia1, Melanie H Wong1, Stephanie A Leavitt1, Yili Xu1, David Koditek1, George J Stepan1, Helen Yu1, Nikos Pagratis1, Sheila Clancy1, Shekeba Ahmadyar1, Terrence Z Cai1,6, Scott Sellers1, Scott A Wolckenhauer1, John Ling1, Christian Callebaut1, Nicolas Margot1, Renee R Ram1, Ya-Pei Liu1, Rob Hyland1, Gary I Sinclair7, Peter J Ruane8, Gordon E Crofoot9, Cheryl K McDonald10, Diana M Brainard1, Latesh Lad1, Swami Swaminathan1, Wesley I Sundquist11, Roman Sakowicz1, Anne E Chester1, William E Lee1, Eric S Daar12, Stephen R Yant13, Tomas Cihlar1.
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.Entities:
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Year: 2020 PMID： 32612233 PMCID： PMC8188729 DOI： 10.1038/s41586-020-2443-1
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962