小柯机器人

美国吉利德科学公司Stephen R. Yant小组取得一项新成果。他们开发出临床靶向艾滋病毒（HIV）衣壳蛋白的长效小分子。这一研究成果在线发表在2020年7月1日出版的《自然》上 。

研究人员介绍了小分子GS-6207，其可破坏HIV衣壳蛋白的功能，由于其高效能、低体内全身清除率和从皮下注射部位释放的动力学缓慢而适合长效治疗。利用X射线晶体学信息，研究人员设计了GS-6207，使其牢固地结合在衣壳蛋白单体之间的保守界面上，从而干扰了衣壳蛋白介导的蛋白之间的相互作用，这对病毒复制周期的多个阶段都是必不可少的。 GS-6207在皮摩尔浓度下对测试的所有HIV-1亚型均表现出抗病毒活性，并且与FDA批准的抗逆转录病毒药物具有高协同且无交叉耐药性的作用。

在1期临床研究中，单次皮下注射GS-6207（450 mg）的单药治疗可在9天后使平均log₁₀转化血浆病毒载量减少2.2，并可以抗病毒活性浓度持续存在于血浆中超过6个月。这些结果为靶向HIV衣壳蛋白功能的疗法提供了临床验证，并证明了GS-6207作为长效剂治疗或预防HIV感染的潜力。

研究人员表示，口服抗逆转录病毒药物可挽救数百万艾滋病毒感染者的生命，并可通过之前感染过的病毒预防新的感染。但是，由于对多种药物的耐药性，一些经过大量治疗的艾滋病毒携带者很少或没有治疗选择。此外，对口服日常方案的依赖性可能会对治疗效果产生负面影响，从而导致病毒学衰竭、耐药性产生和病毒传播以及暴露前预防性用药，从而导致新的感染。新型抗逆转录病毒药物的长效药物可以为经历过治疗的艾滋病毒感染者提供急需的治疗选择，并可以提高依从性。

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

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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