Chimeric Virucides Based on a Novel Theory of Viral Metastability

描述(由申请人提供)：这项HIT提案解决了这样的假设，即旨在结合HIV-1包膜尖峰糖蛋白gp120并同时插入病毒膜的试剂可以向尖峰传递膜指向力，从而导致其自身膜穿孔，导致病毒内容物外流和病毒失活。这一假说是基于这样的观点：(I)成熟的HIV病毒粒子可能受到渗透压，(Ii)病毒尖峰糖蛋白gp41的一个作用是破坏病毒膜的稳定。在这项工作中，我们将设计、测试和优化具有gp120结合结构域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，我们的结果将形成一个基础，在此基础上可以开发出一种全新的杀病毒剂。我们建议基于对病毒生命周期的一种新解释来开发针对HIV-1的病毒药物。这些分子将被设计成劫持病毒的基本特性，通常用于感染细胞，以这种方式在没有目标细胞的情况下“诱使”病毒自毁。如果成功，这项工作将成为开发有效、廉价和易于制造的杀微生物剂的基础，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.