Structure-based discovery and development of HIV-1 gp41 fusion inhibitors

基于结构的 HIV-1 gp41 融合抑制剂的发现和开发

基本信息

批准号：
8536834
负责人：
MIRIAM GOCHIN
金额：
$ 26.52万
依托单位：
TOURO UNIVERSITY OF CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8536834
关键词：
Acquired Immunodeficiency Syndrome Affinity Anti-Retroviral Agents Binding Binding Sites Biochemical Biological Assay Biological Availability Cause of Death Cell Nucleus Cell fusion Cells Characteristics Chemicals Chemokine (C-C Motif) Receptor 5 Chimeric Proteins Collaborations Complex Computer Simulation Coupled Data Detection Development Disease Disease Progression Drug Design Drug Kinetics Drug Targeting Ensure Evaluation Family Fluorescence Generations Goals HIV HIV-1 Half-Life Immune In Vitro Individual Infection Infection prevention Intervention Knowledge Label Lead Letters Libraries Life Cycle Stages Ligand Binding Ligands Link Location Marketing Methods Mission Molecular Bank Molecular Conformation Molecular Models Molecular Weight Oral Outcome Patients Peptides Pharmaceutical Preparations Predisposition Prevalence Prevention strategy Property Proteolysis Public Health Quantitative Structure-Activity Relationship Reaction Relaxation Research Resistance Resistance profile Role San Francisco Site Staging Structure Structure-Activity Relationship Surface Synthesis Chemistry T-20 Techniques Testing Therapeutic Tropism Universities Vaccines Validation Viral Virus Virus Diseases Work assay development base combinatorial computational chemistry cost design drug candidate human disease improved inhibitor/antagonist microbicide molecular modeling novel peptidomimetics prevent process optimization public health relevance resistant strain response scaffold screening small molecule technique development tool transmission process

项目摘要

DESCRIPTION (provided by applicant): This proposal describes the discovery and development of low molecular weight gp41 inhibitors effective against Human Immunodeficiency Virus (HIV-1) fusion. Fusion inhibitors possess excellent characteristics for interrupting HIV transmission and preventing disease progression, since they block initial infection of healthy cells and cell-to-cell spread of infection. Yet there are currently no small molecule inhibitors of fusion, and peptide fusion inhibitors possess some undesirable characteristics such as high cost and susceptibility to proteolysis. The objective of this application is to develop small molecule lead compounds which bind to gp41 with high affinity, preventing the association of N- and C-helical domains that is a central feature of the fusion reaction. The proposal implements a systematic structure-based approach to fusion inhibitor development in three Specific Aims: (1) Modular subsections of the gp41 N-helical coiled coil focused on or around a known hydrophobic pocket will be examined for small molecule binding, through the development of fluorescence, NMR and biological assays to detect and quantitate binding. (2) Novel NMR methods for obtaining explicit structural constraints defining bound ligand conformation and orientation will be developed, providing quantitative structure-activity relationship data for computer modeling and synthesis of improved inhibitors. (3) Compounds with peptidomimetic scaffolds have shown promising binding characteristics in the hydrophobic pocket and will form the basis of design strategies for preparing novel inhibitors, using binding, structural and biological assays for evaluation and optimization. Additional or adjacent hits and structural data obtained during assay application will be incorporated into the lead optimization process. Cell-cell fusion and viral infectivity assays will be applied to provide corroboration of binding studies and to ensure that lead candidates have the desired in vitro properties. This approach will allow testing of the central hypothesis that small molecules binding to the hydrophobic pocket and potentially extending into grooves adjacent to the hydrophobic pocket can be developed into highly potent fusion inhibitors, rivaling peptides. The studies described will provide efficient methods to detect new generations of inhibitors and obtain structural information on their complexes with gp41. Thus they will contribute to a gap in knowledge of the mechanism of gp41 inhibition, since there are currently no experimental data describing the details of small-molecule - gp41 complexes. The significance of this proposal lies in its potential to contribute specifically to HIV-1 fusion inhibitor development and also to the development of techniques applicable to a wide range of Class 1 viruses which use a similar fusion mechanism to HIV-1, a broader goal relevant to NIH's mission of enhancing fundamental knowledge to treat human disease. The long-term goal of the project is to generate drug-like compounds active against HIV-1 fusion, suitable for therapeutic or microbicide use, which could be used to counter or prevent the millions of new infections that occur annually worldwide. PUBLIC HEALTH RELEVANCE: The prevalence of HIV infection remains a significant public health problem due to the development of viral strains resistant to current treatments, and due to spread of the virus from individuals who are unaware they are infected. This proposal seeks to apply structure-aided drug design to develop low molecular weight HIV fusion inhibitors which prevent viral entry and the cell-to-cell spread that causes immune deficiency. Drugs in this class would be useful in microbicides to prevent infection, or could be given orally to treat infection as an alternative to the currently used fusion inhibitor Enfuvirtide(R), which must be given intravenously.

描述（由申请人提供）：该提案描述了针对人免疫缺陷病毒（HIV-1）融合有效的低分子量GP41抑制剂的发现和开发。融合抑制剂具有中断HIV传播和预防疾病进展的良好特征，因为它们阻止了健康细胞的初始感染和感染细胞间传播。然而，目前没有小的融合分子抑制剂，肽融合抑制剂具有某些不良特征，例如高成本和蛋白水解的易感性。该应用的目的是开发具有高亲和力与GP41结合的小分子铅化合物，从而阻止了融合反应的核心特征N-和C螺旋结构域的关联。该提案在三个特定目的中实现了基于系统的融合抑制剂发展的基于系统的结构方法：（1）通过荧光，NMR，NMR和生物学分析的开发和定量结合，将检查小分子结合的GP41 N螺旋线圈的模块化小节。（2）将开发用于定义结合配体构象和方向的明确结构约束的新型NMR方法，从而为计算机建模和合成改进的抑制剂的合成提供定量的结构 - 活性关系数据。（3）具有肽型支架的化合物在疏水口袋中显示出有希望的结合特征，并将使用结合，结构和生物学测定法进行评估和优化，构成制备新型抑制剂的设计策略的基础。在测定应用期间获得的其他或相邻的命中和结构数据将纳入铅优化过程。细胞细胞融合和病毒感染分析将用于提供结合研究的佐证，并确保铅候选者具有所需的体外特性。这种方法将允许测试中心假设，即与疏水口袋结合的小分子并可能延伸到与疏水口袋相邻的凹槽中，可以发展为具有高效的融合抑制剂，具有竞争性的肽。所描述的研究将提供有效的方法来检测新一代的抑制剂，并获得有关其与GP41复合物的结构信息。因此，它们将有助于了解GP41抑制机理的差距，因为目前尚无实验数据描述小分子-GP41复合物的细节。该提案的重要性在于其潜力有可能为HIV-1融合抑制剂开发以及适用于适用于广泛的1类病毒的技术的发展，这些技术使用与HIV-1相似的融合机制，这是与NIH增强基本知识以治疗人类疾病的更广泛的目标。该项目的长期目标是针对HIV-1融合产生类似药物的化合物，适合于治疗或杀生型融合，可用于抵抗或防止全球每年发生的数百万个新感染。公共卫生相关性：由于抗当前治疗的病毒菌株的发展以及病毒的传播，艾滋病毒感染的患病率仍然是一个重大的公共卫生问题，这是从未意识到的那些被感染的人传播。该提案旨在应用结构辅助药物设计来开发低分子量的HIV HIV融合抑制剂，以防止病毒进入和导致免疫缺陷的细胞间扩散。该类别中的药物在菌心以防止感染的菌囊中很有用，或者可以口服感染作为当前使用的融合抑制剂Enfuvirtide（R）的替代品，必须静脉注射。