Design of Potent Divalent Inhibitors of HIV-1

描述(由申请人提供)： 这项拟议工作的目标是检验这样一种假设，即二价分子--呈现两个合适配体副本的分子--将比相应的单价抑制剂更有效地抑制HIV-1。特别是，我们将合成趋化因子受体CCR5的二价拮抗剂。鉴于艾滋病毒-1的高变异率，探索抑制艾滋病毒-1的替代战略是可取的。趋化因子受体CCR5是艾滋病治疗的一个特别有希望的靶点。虽然已经确定了通过CCR5共受体抑制HIV-1进入的分子，但设计与现有药物相比对CCR5具有更高亲和力、表现出更高稳定性且比基于多肽的治疗药物更便宜的抑制剂仍存在挑战。我们已经合成了已知的CCR5拮抗剂的单价衍生物，它们具有反应性的“手柄”(游离氨基)，并保留了抑制CCR5介导的HIV-I感染靶细胞的能力。几项研究表明，二价配体的效力可能比相应的单价配体高几个数量级。因此，设计同时与两个CCR5分子结合并具有高亲和力的二价抑制剂应该是可行的。我们将利用两种策略来合成二价抑制剂。第一种策略涉及化合物的合成，其中CCR5拮抗剂的两个拷贝通过灵活的寡聚(乙二醇基)连接物连接。第二种策略涉及通过寡甘氨酸连接子连接CCR5拮抗剂的两个拷贝。这些连接体比低聚(乙二醇基)连接体更硬，可以用来确定连接体的柔韧性对二价分子效力的影响。我们将在细胞培养系统中测试这些抑制剂的有效性，并在BALB/c小鼠身上测试它们的免疫原性。对CCR5具有较高亲和力的二价HIV-1进入抑制剂可能在预防或延缓耐药病毒株的出现方面发挥重要作用。这些抑制物使靶细胞表面的CCR5二聚化的能力可能会进一步增强它们抑制HIV-1进入的能力。将这些有效的抑制剂与蛋白酶和逆转录酶抑制剂一起“鸡尾酒”服用，可能会对艾滋病的治疗产生重大影响。

DESCRIPTION (provided by applicant): The objective of the proposed work is to test the hypothesis that divalent molecules - molecules presenting two copies of a suitable ligand - will be more potent inhibitors of HIV-1 than the corresponding monovalent inhibitors. In particular, we will synthesize divalent antagonists of the chemokine receptor CCR5. Given the high mutation rate of HIV-1, it is desirable to explore alternative strategies for inhibiting HIV-1. The chemokine receptor CCR5 is a particularly promising target for AIDS therapy. While molecules have been identified that inhibit HIV-1 entry via the CCR5 co-receptor, there are challenges involved in designing inhibitors that have a higher affinity for CCR5 than existing drugs, and that exhibit greater stabilities and are less expensive than peptide-based therapeutics. We have already synthesized monovalent derivatives of known CCR5 antagonists that have reactive "handles" (free amino groups) and retain the ability to inhibit the CCR5-mediated infection of target cells by HIV-I. Several studies have shown that divalent ligands can be several orders of magnitude more potent than the corresponding monovalent ligands. It should therefore be feasible to design divalent inhibitors that will bind to two CCR5 molecules simultaneously, and with high affinity. We will utilize two strategies for the synthesis of divalent inhibitors. The first strategy involves the synthesis of compounds in which two copies of the CCR5 antagonist are connected by flexible oligo (ethylene glycol) linkers. The second strategy involves connecting two copies of the CCR5 antagonist by oligoglycine linkers. These linkers are more rigid than the oligo (ethylene glycol) linkers, and will allow us to determine the influence of the flexibility of the linker on the potency of the divalent molecule. We will test the efficacy of these inhibitors in a cell culture system, and test their immunogenicity in BALB/c mice. Divalent HIV-1 entry inhibitors with a higher affinity for CCR5 may play an important role in preventing or delaying the emergence of drug resistant viral strains. The ability of these inhibitors to dimerize CCR5 on the surface of the target cell may further enhance their ability to inhibit HIV-1 entry. The administration of these potent inhibitors in a 'cocktail' along with protease and reverse transcriptase inhibitors could have a major impact on AIDS therapy.