CCR5 inhibitors that block HIV but not chemokines

CCR5 抑制剂可阻断 HIV，但不能阻断趋化因子

• 批准号: 6746752
• 负责人: PAUL J MADDON
• 金额: $ 30.36万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746752
• 关键词: HIV infections; antiAIDS agent; calcium flux; chemical structure function; chemokine; chemokine receptor; chemotaxis; cytotoxicity; drug design /synthesis /production; human immunodeficiency virus 1; molecular dynamics; pharmacokinetics; receptor binding; small molecule; virus infection mechanism

DESCRIPTION (provided by applicant): A major goal of HIV research is the development of a new generation of antiretroviral agents that target novel stages of the viral replicative cycle. New agents are needed both to combat the growing incidence of HIV strains that are broadly resistant to existing medications and to reduce the considerable toxicities associated with current therapies. HIV entry comprises a cascade of sequential events that provide attractive targets for new therapies. The chemokine receptor CCR5 serves as a critical portal of HIV entry by acting as a fusion coreceptor in conjunction with CD4, the primary receptor for HIV. CCR5 plays a central role in virus transmission and pathogenesis, and thus CCR5-targeted therapies represent a promising new treatment modality. Small-molecule CCR5 inhibitors have been identified previously by screening for inhibition of chemokine binding, which is the natural activity of CCR5. All such molecules are potent CCR5 antagonists that may result in toxicities related to disruption of the chemokine network. Possible side-effects of chronic therapy include loss of CCR5-mediated immune function in patients who are already immunocompromised and overproduction of promiscuous chemokines. To develop inhibitors with a potentially improved therapeutic profile, we adopted the novel approach of identifying molecules that inhibit CCR5's interactions with HIV but not chemokines. The rationale for this approach is provided by the known differences in CCR5 recognition by HIV and chemokines. To achieve this goal, we screened a proprietary library of compounds for inhibition of viral entry using a novel high-throughput assay of HIV membrane fusion. Compounds were later characterized for CCR5 antagonism. This approach has succeeded in the identification of a novel series of compounds that effectively inhibit CCR5-mediated HIV entry without substantial CCR5 antagonism. This compound series thus represents a new class of HIV inhibitors. The overall goal of this Phase 1 project is to optimize this chemical class for increasing antiviral activity while maintaining lack of CCR5 antagonism. This optimization effort will employ an integrated and iterative process of medicinal and computational chemistry coupled with assessment of antiviral potency and chemokine receptor antagonism. The primary criterion for success in this Phase 1 project is the identification of one or more compounds that specifically inhibit CCR5-specific HIV-1 entry at nanomolar concentrations without CCR5 antagonism at micromolar concentrations. Such compounds may offer distinct tolerability and HIV-1 resistance profiles compared to current-generation CCR5 antagonists. Success in the project would provide inhibitors for further optimization to a clinical candidate with the potential to provide an important new form of therapy for HIV-1 infection.

描述（由申请人提供）：HIV 研究的一个主要目标是开发针对病毒复制周期新阶段的新一代抗逆转录病毒药物。需要新的药物来对抗对现有药物具有广泛耐药性的艾滋病毒株不断增加的发病率，并减少与当前疗法相关的相当大的毒性。 HIV 进入包括一系列连续事件，为新疗法提供了有吸引力的靶标。趋化因子受体 CCR5 与 HIV 的主要受体 CD4 一起充当融合共受体，成为 HIV 进入的关键门户。 CCR5 在病毒传播和发病机制中发挥着核心作用，因此 CCR5 靶向疗法代表了一种有前途的新治疗方式。 小分子 CCR5 抑制剂之前已通过筛选趋化因子结合的抑制作用而被鉴定出来，趋化因子结合是 CCR5 的天然活性。所有此类分子都是有效的 CCR5 拮抗剂，可能会导致与趋化因子网络破坏相关的毒性。长期治疗可能产生的副作用包括免疫功能已经受损的患者丧失 CCR5 介导的免疫功能以及过度产生混杂的趋化因子。 为了开发具有潜在改善治疗效果的抑制剂，我们采用了新方法来识别抑制 CCR5 与 HIV 相互作用但不抑制趋化因子的分子。这种方法的基本原理是由 HIV 和趋化因子识别 CCR5 的已知差异提供的。为了实现这一目标，我们使用一种新型的 HIV 膜融合高通量测定法筛选了一个专有的化合物库，用于抑制病毒进入。随后对化合物进行了 CCR5 拮抗作用的表征。这种方法成功地鉴定了一系列新的化合物，这些化合物可以有效抑制 CCR5 介导的 HIV 进入，而不会产生实质性的 CCR5 拮抗作用。因此，该化合物系列代表了一类新的 HIV 抑制剂。 该第一阶段项目的总体目标是优化该化学类别，以提高抗病毒活性，同时保持缺乏 CCR5 拮抗作用。这项优化工作将采用药物和计算化学的集成和迭代过程，并结合抗病毒效力和趋化因子受体拮抗作用的评估。该第一阶段项目成功的主要标准是鉴定一种或多种在纳摩尔浓度下特异性抑制 CCR5 特异性 HIV-1 进入而在微摩尔浓度下不产生 CCR5 拮抗作用的化合物。与当前一代 CCR5 拮抗剂相比，此类化合物可能提供独特的耐受性和 HIV-1 耐药性。该项目的成功将为临床候选者提供进一步优化的抑制剂，有可能为 HIV-1 感染提供一种重要的新疗法。