Discovery and synthesis of small molecule CD4-gp120 antagonists

小分子CD4-gp120拮抗剂的发现与合成

• 批准号: 7356883
• 负责人: Amos B Smith
• 金额: $ 32.04万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7356883
• 关键词: AIDS chemotherapy; Achievement; Acquired Immunodeficiency Syndrome; Address; Agonist; Alkylating Agents; Alkynes; Azides; Bacteriophages; Binding; Binding Sites; Biological; Biosensor; Blood Banks; Calorimetry; Capsid Proteins; Cell fusion; Cell membrane; Cells; Characteristics; Chemicals; Chemistry; Chemokine (C-C Motif) Receptor 5; Collaborations; Collection; Complex; Computer Simulation; Cysteine; Databases; Detection; Development; Diamond; Effectiveness; Elements; Evaluation; Event; Facility Construction Funding Category; Goals; HIV Envelope Protein gp120; HIV-1; Hand; In Situ; Intervention; Knowledge; Laboratories; Lead; Letters; Libraries; Locales; Location; Maps; Measurement; Membrane Fusion; Methods; Modeling; Modification; Molecular; Molecular Conformation; Names; Nature; PO-1; Pathway interactions; Pennsylvania; Peptide aptamers; Peptides; Principal Investigator; Process; Property; Proteins; Protocols documentation; Reaction; Reporting; Research Personnel; Resolution; Roentgen Rays; Role; Scorpions; Screening procedure; Series; Side; Structure; Surface; Thermodynamics; Titrations; Toxin; United States National Institutes of Health; Universities; Vertebral column; Vestibule; Viral; Water; Zinc; analog; base; college; cycloaddition; design; inhibitor/antagonist; innovation; interest; member; mimetics; mimicry; mutant; novel strategies; pandemic disease; peptidomimetics; professor; programs; prospective; protein protein interaction; receptor binding; research study; scaffold; size; small molecule; water channel

Principal Investigator/Program Director (Last, First, Middle): Chaiken, Irwin M / Smith, AmOS B. DESCRIPTION: The Overarching Aim of the Small Molecule Synthesis Thrust for years 12-16 is to discover high potency inhibitors (antagonists) of the HIV-1 viral attachment to the host cell. Two parallel approaches will be taken. The first will entail a screening program to discover perspective new scaffolds for the development of small molecule inhibitors of HIV-1 cell fusion. The library collections and databases for this screen include the Accelys' library comprised of ca. 500,000 small organic compounds, now the property of the Penn Center for Molecular Discovery and the Zinc database. The second approach will involve a series of Specific Aims exploiting iterative structural-based design, synthesis and biological evaluation, carried out in conjunction with members of the Program Project team. These aims include: (1) The development of a strategy for the design and synthesis of small molecule HIV-1 fusion inhibitors by: (a) Exploiting our highly successful, covalent modification/fragment-based SAR/X-ray crystallographic studies, utilizing CD4 mutants and scorpion toxin miniproteins to define the structural characteristics required for binding at the Phe-43 pocket and vestibule of gp120 in the CD4 bound state; and (b) Identifying the structural elements that can occupy the water-filled channel, extending out of the Phe-43 pocket in the gp120-CD4 complex, exploiting both structural-based design tactics and the in situ [3+2] dipolar cycloaddition "click-chemistry" developed by Sharpless; (2) Devise and refine SAR maps of known compounds such as NBD-556 and BMS-806 that either promote or inhibit, respectively, the gp120-CD4-coreceptor entry pathway, with the aim of converting these small molecules into inhibitors of the gp120-CD4 attachment process; (3) Derivatize and conjugate the small molecule NBD-556 and the more potent analogues thereof, discovered by the PO-1 team to be potent CD4 mimetics, with known allosteric inhibitors, such as BMS-806 and 12p1, to convert the NBD-556 small molecule agonist to an antagonist, and (5) Transform the most potent miniprotein and peptide aptamer lead compounds to structurally and functionally congruent antagonists, exploiting a variety of scaffolds, including the Smith-Hirschmann polypyrrolinone. Taken together, the efforts of the Small Molecule Synthesis Thrust (Project 3) in conjunction with other members of the Program Project team will lead to the continued refinement and enhancement of our understanding at the molecular level of the viral-host fusion machinery, and in turn to the development of potentially useful small molecule inhibitors (antagonists), as an effective intervention in the treatment of the AIDS pandemic.

首席调查员 /计划总监（最后，第一，中间）：chaiken，Irwin M / Smith，AmosB。 描述： 小分子合成推力的总体目的12 - 16年是发现高的 HIV-1病毒附着在宿主细胞上的效力抑制剂（拮抗剂）。两种平行方法将是 拍摄。第一个将需要一个筛选计划，以发现开发新的脚手架的观点 HIV-1细胞融合的小分子抑制剂。此屏幕的库集和数据库包括 PRIPELES的图书馆由CA组成。 500,000个小有机化合物，现在是宾夕法尼亚中心的财产 用于分子发现和锌数据库。第二种方法将涉及一系列特定目标 利用基于迭代结构的设计，合成和生物学评估，结合进行 与计划项目团队的成员。这些目的包括：（1）制定 小分子HIV-1融合抑制剂的设计和合成：（a）利用我们的非常成功的， 共价修改/基于片段的SAR/X射线晶体学研究，利用CD4突变体和 蝎子毒素小蛋白质以定义在PHE-43袋中结合所需的结构特征 在CD4结合状态下的GP120的前庭； （b）确定可以占据的结构元素 富含水的通道，从GP120-CD4复合物中的PHE-43口袋延伸，利用了两者 基于结构的设计策略和原位[3+2]偶极环节“点击化学”由 Sharpless; （2）设计和完善已知化合物的SAR地图，例如NBD-556和BMS-806 分别促进或抑制GP120-CD4受体进入途径，目的是转换 这些小分子成GP120-CD4附着过程的抑制剂； （3）衍生和共轭 小分子NBD-556及其更有效的类似物，PO-1团队发现有效 CD4 Mimetics，具有已知的变构抑制剂，例如BMS-806和12P1，可转换NBD-556小 分子激动剂到拮抗剂，（5）转化最有效的微型蛋白和肽适体铅 在结构和功能一致的拮抗剂上的化合物，利用各种脚手架，包括 史密斯·希尔斯曼（Smith-Hirschmann）polypyrolinone。 综上 计划项目团队的成员将导致我们的持续改进和增强我们 在病毒宿主融合机械的分子水平上理解，进而发展 潜在有用的小分子抑制剂（拮抗剂），作为治疗的有效干预 艾滋病大流行。