Chimeric Virucides Based on a Novel Theory of Viral Metastability

描述（由申请人提供）：这个HIT-IT提案解决了一个假设，即设计一种结合HIV-1包膜刺突糖蛋白gp120并同时插入病毒膜的药物可以向刺突传递膜定向力，从而导致其自身膜穿孔，导致病毒内容物流出和病毒失活。这一假设是基于以下观点：(i)成熟的HIV病毒粒子可能受到渗透胁迫，（ii）病毒刺突糖蛋白gp41的一个作用是破坏病毒膜的稳定性。在这项工作中，我们将设计、测试和优化具有gp120结合和膜插入结构域的嵌合体。该项目依赖于高度互联的模拟/实验方法。如果成功，我们的研究结果将为开发出一类全新的杀病毒剂奠定基础。我们建议基于对病毒生命周期的新解释开发针对HIV-1的杀毒剂。这些分子将被设计成劫持通常用于感染细胞的基本病毒特性，以这种方式“诱骗”病毒在缺乏目标细胞的情况下自我毁灭。如果成功，这项工作将为开发有效、廉价和易于制造的杀微生物剂奠定基础，以防止艾滋病的传播。

DESCRIPTION (provided by applicant): This HIT-IT proposal addresses the hypothesis that an agent designed to bind to HIV-1 envelope spike glycoprotein gp120 and insert into the viral membrane simultaneously can deliver a membrane-directed force to the spike, thereby causing it to porate its own membrane, resulting in outflow of viral contents and deactivation of the virus. This hypothesis is based on the vision that (i) the mature HIV virion is likely osmotically stressed, and (ii) one role of the viral spike glycoprotein gp41 is to destabilize the viral membrane. In this work, we will design, test and optimize chimerae with gp120-binding and membrane-insertion domains. The project relies on a highly interconnected simulation/experimentation approach. If successful, our results will form the basis upon which a completely new class of virucidal agents can be developed. We propose to develop virucides against HIV-1 based upon a novel interpretation of the viral life cycle. These molecules will be designed to hijack essential viral properties, normally used to infect cells, in such a way as to "trick" the virus into self-destructing in the absence of a target cell. If successful, this work will form the basis for the development of potent, cheap and easy-to-manufacture microbicides for preventing the spread of AIDS.