Rational design of viral inhibitors: Application to SARS

开发能够有效地针对和预防病毒感染的合理方法是一种 WRCE的战略目标。尽管理性设计的努力偶尔会取得成功，但一个关键 缺点是与蛋白质构象的动态性质相关的困难。也就是说，病毒 蛋白质靶标(通常是包膜蛋白)的行为不像用来描绘的静态结构 他们。相反，这些蛋白质是动态的，并经历构象波动。这构成了 为结构不同的靶标设计配基明显困难--配基必须 与蛋白质的一个低能构象或多个高能构象兼容 以便产生足够高的结合亲和力。在这里，这个问题通过一个唯一的 计算方法，称为Corex_Design，是在过去十年中开发的，它 将蛋白质和多肽模拟为构象状态的集合。 人蛋白(PrP)抑制剂设计及冠状病毒制剂的最新研究 严重急性呼吸综合征(SARS)，已经提供了Corex_Design是 能够；1)确定热力学上相容的潜在结合位点(S)，2)构象设计 与该位点结构相容的限制性二硫键交联型环肽配体，以及3) 优化序列以最大限度地提高蛋白质和多肽之间的构象兼容性。 使用这个工具，我们能够成功地设计出由PrP形成的有效的淀粉样蛋白形成抑制剂，我们 已经收集到了针对SCOV的抗病毒活性的初步结果，SCOV是这个项目的目标之一 求婚。 本项目的目标是演示Corex_Design可以作为一种通用策略应用于 抗病毒药物的发展。尽管这种新的设计工具原则上可以应用于任何系统 在有关靶的结构信息已知的情况下，在这里将其应用于包膜蛋白的结构域3 登革2型病毒(DN2V)的S蛋白和SCOV的S蛋白(S)。在资助期间，我们将 证明设计的多肽在基于细胞的分析中的有效性，并在赠款过程中 将在动物实验中测试先导化合物。 相关性(请参阅说明)： NIAID A、B和C类病毒每年造成数百万人感染。很少有抗病毒药物 治疗方法可以用来治疗这些感染。这里描述的方法利用了一个独特的 抗病毒药物开发中的计算建模策略。这种方法的成功 可以为抗击感染提供新的途径，从而拯救生命

The development of rational approaches that can effectively target and prevent viral infection is a strategic objective of the WRCE. Although rational design efforts have met with occasional success, a key shortcoming is the difficulty associated with the dynamic nature of protein conformation. Namely, the viral protein targets (usually envelope proteins) do not behave as the static structures that are used to depict them. Instead, these proteins are dynamic and experience conformational fluctuations. This poses the obvious difficulty associated with designing a ligand for a structurally heterogeneous target-the ligand must be compatible with either one low energy conformation of the protein or multiple higher energy conformations in order to result in a high enough binding affinity. Here, this problem is addressed with a unique computational approach, called COREX_Design, that has been developed over the past decade, and which models proteins and peptides as ensembles of conformational states. Recent studies on the design of inhibitors to the human prion protein (PrP), and the coronavirus agent of severe acute respiratory syndrome (SARS) (SCoV), have provided proof-of-principle that COREX_Design is able to; 1) identify "thermodynamically compatible" potential binding site(s), 2) design a conformationally constrained, disulfide cross-linked cyclic peptide ligand that is structurally compatible with this site, and 3) optimize the sequence to maximize the conformational compatibility between the protein and the peptide. Using this tool, we were able to successfully design potent inhibitors of amyloid formation by PrP, and we have collected strong preliminary results for antiviral activity against SCoV, one of the targets of this proposal. The goal of this project is to demonstrate that COREX_Design can be applied as a general strategy to the development of antiviral agents. Although this new design tool can in principle be applied to any system where structural information is known about the target, it is applied here to domain 3 of the envelope protein of dengue 2 virus (DN2V) and the spike (S) protein of SCoV. During the period of funding, we will demonstrate the efficacy of the designed peptides in cell based assays, and over the course of the grant we will test lead compounds in animal studies. RELEVANCE (See instructions): NIAID Category A, B and C viruses are responsible for millions of infections each year. Few antiviral therapeutics are available to treat these infections. The approach described here leverages a unique computational modeling strategy into the development of antiviral agents. The success of this approach could offer new avenues for combating infections and thus saving lives