Development of novel small-molecule inhibitors of HIV-1 fusion as microbicides

作为杀微生物剂的新型 HIV-1 融合小分子抑制剂的开发

• 批准号: 8892301
• 负责人: Min Lu
• 金额: $ 63.6万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892301
• 关键词: Acquired Immunodeficiency Syndrome; Address; Anti-Retroviral Agents; Antiviral Agents; Antiviral resistance; Binding; Biological Assay; CCR5 gene; Cell fusion; Cells; Cervical; Clinical; Clinical Trials; Complex; Consensus; Data; Development; Drug Formulations; Drug resistance; Drug-sensitive; Effectiveness; Environment; Evolution; Gel; Generations; Genital system; Goals; HIV Envelope Protein gp120; HIV-1; Health; Human; In Vitro; Infection; Inhibitory Concentration 50; Local Microbicides; Macaca; Mammalian Cell; Mediating; Modeling; Modification; Molecular; Molecular Weight; Mus; Oryctolagus cuniculus; Peptides; Pharmaceutical Preparations; Procedures; Production; Property; Pyrrolidinones; Research; Resistance; Sexual Transmission; Site; Solubility; Staging; Structure; Structure-Activity Relationship; Sulfonamides; T-Lymphocyte; Tenofovir; Testing; Therapeutic Intervention; Tissues; Toxic effect; Toxicity Tests; Vaccines; Vagina; Virus; Vision; Woman; Work; analog; base; chemical property; chemical stability; cost; cytotoxicity; design; efficacy testing; env Glycoproteins; human female; improved; in vivo; inhibitor/antagonist; interest; irritation; microbicide; mouse model; novel; prevent; prophylactic; receptor; research study; simian human immunodeficiency virus; small molecule; transmission process; viral resistance

DESCRIPTION (provided by applicant): Positive data from the CAPRISA 004 trial of tenofovir gel have stimulated tremendous interest in development of HIV-1 entry inhibitors as topical microbicides or even systematically delivered prophylactic drugs to prevent the sexual transmission of HIV-1. While considerable effort has gone into discovering and developing small-molecule agents that inhibit HIV-1 envelope glycoprotein (Env)-mediated virus-cell fusion by targeting the gp41 subunit, none of these compounds has successfully advanced in clinical development of topical microbicides. The long-term objective of this research plan is to develop a safe and highly effective low-molecular-weight gp41 fusion inhibitor for use as an active ingredient in anti-HIV-1 microbicides. In preliminary work, we have identified the novel target of the HIV-1 fusion inhibitor phenyl sulfonamide derivative (PSD) that was first identified in an Env-mediated cell-cell fusion inhibitor screen. This compound binds to a conserved hydrophobic pocket within a subdomain of gp41. We demonstrate that new PSD analogs potently inhibit in vitro infection of human T cells by primary HIV-1 isolates with different geographic origins and co-receptor requirements. We have defined a provisional structure-activity relationship (SAR) for PSDs. The structural data and SAR suggest PSD modifications that could improve potency and pharmacological properties. We propose to leverage the structural data, SAR and synthetic procedures developed in preliminary work to design, synthesize and evaluate novel PSD analogs that have enhanced efficacy against a broad-spectrum of sexually transmitted drug-sensitive and drug-resistant HIV-1 strains. To achieve our goals we have developed the following specific aims: 1. To utilize the structural principles of gp41 fusion inhibitor-target interactions to optimize the antiviral potency and microbicidal properties of PSDs. 2. To evaluate the potency, breadth and synergistic interactions, the molecular basis for antiviral activity and resistance, the physicochemical properties and the in vitro and in vivo toxicity of novel PSDs. 3. To evaluate the effectiveness of novel PSDs in mucosal protection against HIV-1 infection in vitro and in vivo. These aims are motivated by the opportunity to validate the novel gp41 hydrophobic pocket as the target of inhibitor binding, based on our identification of specific inhibitor-target site interactions that underlie structure-based antagonism of HIV-1 gp41 function in cell entry and that can be strengthened to improve potency and broad-spectrum activity. Our ability to piece together a quantitative picture of these inhibitor-target interactions sets the stge for rational development of new small-molecule gp41 fusion inhibitors for prophylactic and/or therapeutic intervention of HIV-1 infection.

描述（由申请人提供）：替诺福韦凝胶 CAPRISA 004 试验的积极数据激发了人们对开发 HIV-1 进入抑制剂作为局部杀菌剂甚至系统性递送预防药物以防止 HIV-1 性传播的极大兴趣。尽管人们在发现和开发通过靶向 gp41 亚基来抑制 HIV-1 包膜糖蛋白 (Env) 介导的病毒与细胞融合的小分子药物方面付出了相当大的努力，但这些化合物均未成功推进局部杀菌剂的临床开发。该研究计划的长期目标是开发一种安全高效的低分子量gp41融合抑制剂，用作抗HIV-1杀菌剂的活性成分。在前期工作中，我们已经确定了 HIV-1 融合抑制剂苯基磺酰胺衍生物 (PSD) 的新靶点，该靶点首次在 Env 介导的细胞间融合抑制剂筛选中被发现。该化合物与 gp41 子结构域内的保守疏水口袋结合。我们证明，新的 PSD 类似物可有效抑制具有不同地理来源和辅助受体要求的原代 HIV-1 分离株对人类 T 细胞的体外感染。我们为 PSD 定义了临时结构-活性关系 (SAR)。结构数据和 SAR 表明 PSD 修饰可以提高效力和药理特性。我们建议利用前期工作中开发的结构数据、SAR 和合成程序来设计、合成和评估新型 PSD 类似物，这些类似物可增强对广谱性传播药物敏感和耐药 HIV-1 菌株的功效。为了实现我们的目标，我们制定了以下具体目标： 1. 利用 gp41 融合抑制剂-靶点相互作用的结构原理来优化 PSD 的抗病毒效力和杀菌特性。 2. 评估新型PSD的效力、广度和协同相互作用、抗病毒活性和耐药性的分子基础、理化特性以及体外和体内毒性。 3. 评价新型PSD在体外和体内针对HIV-1感染的粘膜保护作用的有效性。这些目标的动机是有机会验证新型 gp41 疏水口袋作为抑制剂结合的目标，基于我们对特定抑制剂-目标位点相互作用的识别，该相互作用是细胞进入中 HIV-1 gp41 功能基于结构的拮抗作用的基础，并且可以得到加强，以提高效力和广谱活性。我们能够拼凑出这些抑制剂-靶点相互作用的定量图景，为合理开发用于预防和/或治疗干预 HIV-1 感染的新型小分子 gp41 融合抑制剂奠定了基础。