一种高效长效小分子HIV-1衣壳抑制剂，在人源化小鼠模型中具有疗效。该成果由美国Gilead Sciences公司Stephen R. Yant研究团队牵头研究获得。2019年9月出版的《自然—医学》在线发表了这一研究成果。

研究团队报告了GS-CA1，一种新的原型小分子HIV衣壳抑制剂，具有抗HIV-2和所有主要HIV-1类型的特殊效力，包括对目前临床使用的抗逆转录病毒药物具有抗性的病毒变体。作用机制研究表明，GS-CA1直接与HIV-1衣壳结合，并干扰衣壳介导的病毒DNA核输入，HIV颗粒产生和有序衣壳的组装。GS-CA1在体外选择不适合的对GS-CA1耐药的衣壳变体，其对其它类型的ARV仍然完全敏感。其高代谢稳定性和低溶解度，使得在单次皮下给药后小鼠中的持续药物释放成为可能。在感染HIV-1的小鼠模型中，GS-CA1作为一种长效注射单药疗法显示出了很高的抗病毒效果，其效果优于长效利福韦林。总之，这些结果证明了超能衣壳抑制剂作为治疗HIV-1感染的新型长效药物的潜力。

据悉，艾滋病病毒感染者（PLWH）对每天服用药物带来的负担和耻辱表示担忧，并且可能会出现药物疲劳，导致治疗依从性不理想，以及耐药病毒变异的出现。这些都限制了未来的治疗方案。为此，人们对长效抗逆转录病毒药物(ARV)有着浓厚的兴趣，因为这种药物的使用频率较低。

附：英文原文

Title: A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model

Author: Stephen R. Yant, Andrew Mulato, Derek Hansen, Winston C. Tse, Anita Niedziela-Majka, Jennifer R. Zhang, George J. Stepan, Debi Jin, Melanie H. Wong, Jill M. Perreira, Eric Singer, Giuseppe A. Papalia, Eric Y. Hu, Jim Zheng, Bing Lu, Scott D. Schroeder, Kevin Chou, Shekeba Ahmadyar, Albert Liclican, Helen Yu, Nikolai Novikov

Issue&Volume: 2019/09

Abstract: People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options13. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection. A new compound that inhibits HIV capsid assembly and nuclear transport functions offers potential as a long-acting antiretroviral.

DOI: 10.1038/s41591-019-0560-x

Source:https://www.nature.com/articles/s41591-019-0560-x