TO INVESTIGATE LONG-RANGE DYNAMIC EFFECTS FROM ANTIVIRAL COMPOUNDS BOUND IN THE

研究结合在体内的抗病毒化合物的长期动态影响

• 批准号: 7956252
• 负责人: CAROL B. POST
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956252
• 关键词: Antiviral Agents; Binding; Biomedical Research; Capsid; Charge; Common Cold; Complex; Computer Retrieval of Information on Scientific Projects Database; Coxsackie Viruses; Family Picornaviridae; Funding; Grant; High Performance Computing; Human; Institution; Life Cycle Stages; Molecular; Mutagenesis; Pharmacologic Substance; Process; Research; Research Personnel; Resources; Rhinovirus; Source; Structure; United States National Institutes of Health; Viral Proteins; Virus; member; receptor; rhinovirus viral protein 1; simulation; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human rhinovirus (HRV) and coxsackievirus (CV) are two members of the Picornaviridae family: HRV, a causative agent of the common cold, is a well studied pharmaceutical target with considerable structural information known about its complexes with antiviral compounds and receptor. Small molecule compounds bind to the HRV viral protein 1 (VP1) in an internal pocket located near the 5-fold symmetry axis of the capsid shell, and interrupt the virus life cycle by inhibiting the uncoating process. We propose the molecular mechanism for this antiviral activity involves long-range effects of antiviral compounds on conformational dynamics. Receptor recognition is another primary component of the virus life cycle. HRV and CV seem to recognize receptor largely by charge complementarity, but results from mutagenesis of a Lys residue cannot be explained from the known crystal structures. Conformational fluctuations of residues at the 5-fold axis are decreased when antiviral compounds occupy the VP1 pocket even though the pocket is not in direct contact with these residues. These long-range effects may be the origin of the antiviral activity of these compounds. The effects will be explored by MD simulations of the pentameric unit of HRV and complexes of HRV with WIN antiviral compounds. Similar studies on coxsackievirus A21 (CVA21) are also planned.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 人类鼻病毒（HRV）和Coxsackievievirus（CV）是Picornaviridae家族的两个成员：HRV是普通感冒的致病药物，是一个经过良好研究的药物靶标，具有有关其抗病毒化合物和受体的复合物已知的相当大的结构信息。小分子化合物在位于衣壳壳的5倍对称轴附近的内部口袋中与HRV病毒蛋白1（VP1）结合，并通过抑制不涂层过程来中断病毒生命周期。我们提出了这种抗病毒活性的分子机制涉及抗病毒化合物对构象动力学的远距离影响。受体识别是病毒生命周期的另一个主要组成部分。 HRV和CV似乎在很大程度上通过电荷互补性识别受体，但是无法从已知的晶体结构中解释LYS残基的诱变所致。当抗病毒化合物占据VP1袋时，即使口袋与这些残基直接接触，抗病毒化合物占据了5倍轴的残基的构象波动。这些远程作用可能是这些化合物抗病毒活性的起源。该效果将通过HRV的五型人群和HRV复合物的MD模拟与Win抗病毒化合物进行探索。还计划了对Coxsackievivirus A21（CVA21）的类似研究。