科學家研發出靶向愛滋病毒衣殼蛋白的長效小分子
作者：
小柯機器人發布時間：2020/7/3 9:39:00
美國吉利德科學公司Stephen R. Yant小組取得一項新成果。他們開發出臨床靶向愛滋病毒（HIV）衣殼蛋白的長效小分子。這一研究成果在線發表在2020年7月1日出版的《自然》上 。
研究人員介紹了小分子GS-6207，其可破壞HIV衣殼蛋白的功能，由於其高效能、低體內全身清除率和從皮下注射部位釋放的動力學緩慢而適合長效治療。利用X射線晶體學信息，研究人員設計了GS-6207，使其牢固地結合在衣殼蛋白單體之間的保守界面上，從而幹擾了衣殼蛋白介導的蛋白之間的相互作用，這對病毒複製周期的多個階段都是必不可少的。 GS-6207在皮摩爾濃度下對測試的所有HIV-1亞型均表現出抗病毒活性，並且與FDA批准的抗逆轉錄病毒藥物具有高協同且無交叉耐藥性的作用。
在1期臨床研究中，單次皮下注射GS-6207（450 mg）的單藥治療可在9天後使平均log10轉化血漿病毒載量減少2.2，並可以抗病毒活性濃度持續存在於血漿中超過6個月。這些結果為靶向HIV衣殼蛋白功能的療法提供了臨床驗證，並證明了GS-6207作為長效劑治療或預防HIV感染的潛力。
研究人員表示，口服抗逆轉錄病毒藥物可挽救數百萬愛滋病毒感染者的生命，並可通過之前感染過的病毒預防新的感染。但是，由於對多種藥物的耐藥性，一些經過大量治療的愛滋病毒攜帶者很少或沒有治療選擇。此外，對口服日常方案的依賴性可能會對治療效果產生負面影響，從而導致病毒學衰竭、耐藥性產生和病毒傳播以及暴露前預防性用藥，從而導致新的感染。新型抗逆轉錄病毒藥物的長效藥物可以為經歷過治療的愛滋病毒感染者提供急需的治療選擇，並可以提高依從性。
附：英文原文
Title: Clinical targeting of HIV capsid protein with a long-acting small molecule
Author: 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. Villaseor, 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
Issue&Volume: 2020-07-01
Abstract: Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1,2,3,4,5. 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 infections1,2,4,7,8,9. 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.
DOI: 10.1038/s41586-020-2443-1
Source: https://www.nature.com/articles/s41586-020-2443-1