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

可以有效靶向和预防病毒感染的理性方法的发展是 WRCE的战略目标。尽管理性的设计工作已经取得了偶尔的成功，但这是关键缺点是与蛋白质构象的动态性质相关的困难。即病毒蛋白质靶标（通常包膜蛋白）并不是用来描绘的静态结构他们。相反，这些蛋白质是动态的，并且经历了构象的波动。这构成了与为结构异质靶标设计配体相关的明显困难 - 必须与蛋白质的一个低能构象或多个较高能量构象兼容为了产生足够高的结合亲和力。在这里，这个问题以独特的在过去十年中已经开发的计算方法，称为corex_design，哪个模型蛋白质和肽作为构象状态的集合。最近关于人类prion蛋白抑制剂（PRP）的抑制剂的研究和冠状病毒剂严重的急性呼吸综合征（SARS）（SCOV）提供了corex_design为能够1）识别“热力学兼容”电势结合位点，2）在构象上设计受约束，二硫键交联的环状肽配体在结构上与该位点兼容，3）优化序列，以最大化蛋白质与肽之间的构象兼容性。使用此工具，我们能够通过PRP成功设计淀粉样蛋白形成的有效抑制剂，我们对SCOV的抗病毒活性收集了强烈的初步结果，这是其中之一提议。该项目的目的是证明Corex_design可以作为一般策略应用于抗病毒药物的发展。尽管该新设计工具原则上可以应用于任何系统如果知道目标的结构信息，则在此处应用于包膜蛋白的域3 登革热2病毒（DN2V）和SCOV的尖峰蛋白。在资金期间，我们将证明设计肽在基于细胞的测定中的功效，以及在赠款的过程中将测试动物研究中的铅化合物。相关性（请参阅说明）： NIAID类别A，B和C病毒每年导致数百万感染。很少的抗病毒可以治疗这些感染。这里描述的方法利用了独特的计算建模策略到抗病毒药物的发展。这种方法的成功可以提供新的途径来打击感染，从而挽救生命