Elucidating the molecular mechanisms of small-molecule disruption of viral replication machinery

阐明小分子破坏病毒复制机制的分子机制

• 批准号: 10468709
• 负责人: Juan Roberto Perilla Jimenez
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2023-03-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468709
• 关键词: Amino Acid Sequence; Amino Acid Substitution; Anti-Retroviral Agents; Antiviral Agents; Automobile Driving; Behavior; Binding; Biological Assay; Biological Process; Capsid; Capsid Proteins; Cell physiology; Cells; Cellular biology; Chemicals; Complex; Computer Models; Computers; Computing Methodologies; Cryoelectron Microscopy; Development; Electron Microscopy; HIV; HIV Protease; HIV-1; Infection; Integrase; Knowledge; Life Cycle Stages; Macromolecular Complexes; Mediating; Methodology; Methods; Modeling; Molecular; Patients; Peptides; Perilla; Pharmaceutical Preparations; Phase; Phytic Acid; Process; Property; Proteins; Research; Resistance; Retroviridae; Structure; System; Techniques; Therapeutic; Validation; Viral; Virus; Virus Assembly; Virus Replication; Work; alpha helix; design; fitness; human disease; human pathogen; in vivo; macromolecular assembly; models and simulation; molecular dynamics; molecular scale; new therapeutic target; novel; particle; pathogen; prevent; protein complex; simulation; small molecule; small molecule therapeutics; structural biology; success; therapeutic target; tool; virology; virus related cancer

5. Elucidating the molecular mechanisms of small-molecule disruption of viral replication machinery Project Leader: Juan Perilla (CBC) Computational modeling and simulations provide a powerful toolset to determine the atomistic mechanisms underlying biological processes, such as those that occur during the life cycle of a pathogen. Likewise, computational methods can be leveraged to reveal the mechanisms by which these processes are altered or disrupted by small-molecule therapeutics. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the replication machinery essential to a highly relevant human pathogen, namely HIV-1. Despite the success of several antiretrovirals, the virus has evolved resistance to all known drugs. Remarkably, not a single drug has been developed against large protein assemblies like the viral capsid therefore providing an unexploited therapeutic target. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the capsid-related replication machinery essential to HIV. Importantly, the proposed work is not only relevant for HIV patients as HIV serves as a model for other human diseases, including virus-related cancer. In addition, the cutting-edge methods developed herein will be directly applicable to other virus and bacterial assemblies.

5. 阐明小分子破坏病毒复制的分子机制