CCR5 inhibitors that block HIV but not chemokines

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菌株的日益增长的发病率，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点。趋化因子受体CCR 5通过与HIV的主要受体CD 4结合作为融合辅助受体而充当HIV进入的关键门户。CCR 5在病毒传播和发病机制中起着核心作用，因此CCR 5靶向治疗代表了一种有前途的新治疗方式。 先前已经通过筛选趋化因子结合的抑制来鉴定小分子CCR 5抑制剂，趋化因子结合是CCR 5的天然活性。所有这些分子都是有效的CCR 5拮抗剂，可能导致与趋化因子网络破坏相关的毒性。慢性治疗可能的副作用包括免疫功能低下患者CCR 5介导的免疫功能丧失和混杂趋化因子过度产生。 为了开发具有潜在改善治疗特性的抑制剂，我们采用了识别抑制CCR 5与HIV相互作用而不是趋化因子的分子的新方法。这种方法的基本原理是由HIV和趋化因子识别CCR 5的已知差异提供的。为了实现这一目标，我们筛选了一个专有的化合物库，使用一种新的HIV膜融合的高通量测定抑制病毒进入。随后对化合物的CCR 5拮抗作用进行了表征。这种方法已成功鉴定出一系列新型化合物，这些化合物可有效抑制CCR 5介导的HIV进入，而不会产生实质性的CCR 5拮抗作用。因此，该化合物系列代表了一类新的HIV抑制剂。 该1期项目的总体目标是优化这种化学类别，以增加抗病毒活性，同时保持缺乏CCR 5拮抗作用。这种优化工作将采用药物和计算化学的集成和迭代过程，再加上抗病毒效力和趋化因子受体拮抗作用的评估。该1期项目成功的主要标准是鉴定一种或多种化合物，其在纳摩尔浓度下特异性抑制CCR 5特异性HIV-1进入，而在微摩尔浓度下无CCR 5拮抗作用。与当前一代的CCR 5拮抗剂相比，这些化合物可以提供不同的耐受性和HIV-1抗性特征。该项目的成功将为进一步优化临床候选药物提供抑制剂，并有可能为HIV-1感染提供重要的新治疗形式。

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.