Project 1. Maturation and Assembly

项目 1. 成熟和组装

• 批准号: 10653262
• 负责人: Barbie K. Ganser-Pornillos
• 金额: $ 51.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653262
• 关键词: Binding; Binding Proteins; Binding Sites; Biochemical; Biochemistry; Biological Assay; Biological Metamorphosis; CASP1 gene; Capsid; Complement; Complex; Computational Technique; Cryoelectron Microscopy; Cytoplasmic Tail; Data; Development; Disulfides; Drug resistance; Enzymes; Generations; Genetic Polymorphism; Goals; HIV; HIV-1; HIV-1 integrase; Individual; Integrase; Integrase Inhibitors; Investigation; Knowledge; Magic; Mediating; Molecular; Mutation; Nucleocapsid; Pathway interactions; Peptide Hydrolases; Play; Process; Protein Inhibition; Proteins; RNA; RNA-Directed DNA Polymerase; RNA-Protein Interaction; Research Personnel; Resistance; Ribonucleoproteins; Role; Series; Site; Structure; Techniques; Testing; Variant; Viral; Viral Matrix Proteins; Viral Physiology; Viral Proteins; Virion; Virus; Virus Replication; Visualization; Work; crosslinking and immunoprecipitation sequencing; design; dimer; drug candidate; experimental study; genomic RNA; glycoprotein 41; imaging approach; improved; inhibitor; insight; mutant; novel; particle; pol Gene Products; prevent; solid state nuclear magnetic resonance; superresolution microscopy; viral resistance; virology

Project 1 – HIV-1 Maturation and Assembly The overall goal of this project is to identify and exploit key, potentially druggable complexes and interactions that are present during HIV-1 assembly and maturation, including Gag and its maturation intermediates, the viral ribonucleoprotein (vRNP) complex, and the matrix (MA)-glycoprotein 41 (gp41) cytoplasmic tail interaction. The proposed studies are an integrated effort from 11 PCHPI investigators and four cores (NMR, CryoEM/ET, Computational, and HIV Virology). The specific aims are designed to i) understand the molecular, biochemical, and structural basis for maturation inhibitor (MI) and allosteric integrase inhibitor (ALLINI) activity and resistance pathways; ii) define the organization of RNA and proteins in the viral ribonucleoprotein complex (vRNPs) and at specific stages of maturation; and iii) characterize the interaction between the MA domain of Gag and the cytoplasmic tail of gp41. The structural and mechanistic knowledge gained through the proposed work will inform the development of novel MIs and ALLINIs with improved antiviral potency and potentially guide approaches to inhibit protein interactions in HIV-1 vRNPs and in MA-gp41 complexes.

项目1 - HIV-1成熟和组装 这个项目的总体目标是识别和利用关键的，潜在的药物复合物和相互作用 在HIV-1组装和成熟过程中存在的，包括Gag及其成熟中间体，病毒 核糖核蛋白（vRNP）复合物和基质（MA）-糖蛋白41（gp 41）胞质尾相互作用。的 提出的研究是来自11个PCHPI研究者和四个岩心（NMR，CryoEM/ET， 计算和HIV病毒学）。具体目标是i）了解分子，生物化学， 以及成熟抑制剂（MI）和变构整合酶抑制剂（ALLINI）活性和抗性的结构基础 ii）定义病毒核糖核蛋白复合物（vRNP）中RNA和蛋白质的组织， iii）表征Gag的MA结构域与Gag的MA结构域之间的相互作用; gp 41的胞质尾区。通过拟议的工作获得的结构和机械知识将告知 开发具有改善的抗病毒效力的新型MI和ALLINI， 抑制HIV-1 vRNP和MA-gp 41复合物中的蛋白质相互作用。