Rational design of viral inhibitors: Application to SARS

病毒抑制剂的合理设计：在SARS中的应用

基本信息

批准号：
7649123
负责人：
VINCENT J. HILSER
金额：
$ 13.18万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649123
关键词：
Address Affinity Animal Model Animals Antiviral Agents Binding Binding Proteins Binding Sites Biological Assay Calorimetry Categories Cells Chimeric Proteins Class Collaborations Compatible Complex Computer Simulation Coronavirus Cyclic Peptides Data Dengue Development Disulfides Funding Generations Generic Drugs Goals Grant Human In Vitro Infection Instruction Lead Libraries Life Ligands Modeling Molecular Conformation National Institute of Allergy and Infectious Disease Nature Peptides Prions Protein Conformation Protein Dynamics Proteins Range Severe Acute Respiratory Syndrome Site Structure System Technology Testing Therapeutic Thermodynamics Titrations Validation Variant Viral Proteins Virus Virus Diseases Virus Inhibitors X-Ray Crystallography amyloid formation analog base crosslink design env Gene Products experience in vivo inhibitor/antagonist novel pathogen peptide analog prevent receptor binding success tool

项目摘要

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

开发能够有效针对和预防病毒感染的合理方法是一个重要的任务 WRCE 的战略目标。尽管合理的设计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，病毒蛋白质目标（通常是包膜蛋白）的行为并不像用于描述的静态结构那样他们。相反，这些蛋白质是动态的并且会经历构象波动。这提出了与为结构异质靶标设计配体相关的明显困难是配体必须与蛋白质的一种低能构象或多种高能构象相容以产生足够高的结合亲和力。在这里，这个问题通过一个独特的解决方案称为 COREX_Design 的计算方法在过去十年中得到了发展，并且将蛋白质和肽建模为构象状态的整体。人朊病毒蛋白（PrP）抑制剂的设计以及冠状病毒制剂的最新研究严重急性呼吸系统综合症 (SARS) (SCoV) 提供了原理证明，证明 COREX_Design 是能够； 1) 识别“热力学相容”的潜在结合位点，2) 设计构象与该位点结构相容的受限二硫键交联环肽配体，以及 3) 优化序列以最大化蛋白质和肽之间的构象相容性。使用这个工具，我们能够成功地设计出 PrP 淀粉样蛋白形成的有效抑制剂，并且我们已经收集了针对 SCoV 的抗病毒活性的强有力的初步结果，SCoV 是本次研究的目标之一提议。该项目的目标是证明 COREX_Design 可以作为通用策略应用于抗病毒药物的开发。虽然这种新的设计工具原则上可以应用于任何系统如果目标的结构信息已知，则将其应用于包膜蛋白的结构域 3 登革热 2 病毒 (DN2V) 和 SCoV 的刺突 (S) 蛋白。在资助期间，我们将证明了设计的肽在基于细胞的测定中的功效，并且在资助过程中，我们将在动物研究中测试先导化合物。相关性（参见说明）： NIAID A、B 和 C 类病毒每年导致数百万例感染。抗病毒药很少有治疗方法可以治疗这些感染。这里描述的方法利用了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提供抗击感染从而拯救生命的新途径