CCR5 inhibitors that block HIV but not chemokines

描述(由申请人提供)：艾滋病毒研究的一个主要目标是开发针对病毒复制周期的新阶段的新一代抗逆转录病毒药物。既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毒株的日益增长的发病率，也需要新的药物来减少与目前的治疗方法相关的相当大的毒性。HIV进入包括一系列连续事件，这些事件为新疗法提供了有吸引力的靶点。趋化因子受体CCR5通过与HIV的主要受体CD4共同作用，作为HIV进入的关键门户。CCR5在病毒传播和发病机制中起着核心作用，因此针对CCR5的治疗代表了一种很有前途的新的治疗模式。 小分子CCR5抑制剂之前已经通过筛选抑制趋化因子结合来鉴定，趋化因子结合是CCR5的自然活性。所有这些分子都是强有力的CCR5拮抗剂，可能会导致与破坏趋化因子网络有关的毒性。慢性治疗的可能副作用包括已经免疫受损的患者失去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特征的抑制剂，我们采用了一种新的方法，即识别抑制CCR5‘S与艾滋病毒相互作用的分子，但不抑制趋化因子。这种方法的原理是由艾滋病毒和趋化因子在识别CCR5方面的已知差异提供的。为了实现这一目标，我们使用一种新的高通量HIV膜融合分析方法筛选了一个专有的化合物文库，用于抑制病毒进入。化合物后来被鉴定为CCR5拮抗剂。这种方法已经成功地鉴定了一系列新的化合物，这些化合物有效地抑制了CCR5介导的艾滋病毒进入，而没有实质性的CCR5拮抗作用。因此，该化合物系列代表了一类新的艾滋病毒抑制剂。 这个第一阶段项目的总体目标是优化这一化学类别，以增加抗病毒活性，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综合和迭代过程，并结合抗病毒效力和趋化因子受体拮抗的评估。这一阶段项目成功的主要标准是识别出一种或多种化合物，这些化合物在纳摩尔浓度下专门抑制CCR5特异性HIV-1进入，而在微摩尔浓度没有CCR5拮抗作用。与当前一代的CCR5拮抗剂相比，这些化合物可能提供不同的耐受性和对HIV-1的抗药性。该项目的成功将为进一步优化临床候选药物提供抑制剂，有可能为艾滋病毒-1感染提供一种重要的新形式的治疗。

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.