Design of Potent Divalent Inhibitors of HIV-1

HIV-1 有效二价抑制剂的设计

• 批准号: 6654232
• 负责人: Ravi S. Kane
• 金额: $ 7.73万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654232
• 关键词: AIDS therapy; aminoacid; antiAIDS agent; antigen antibody reaction; chemical structure function; chemical synthesis; cytokine receptors; drug design /synthesis /production; human immunodeficiency virus 1; inhibitor /antagonist; laboratory mouse; protein structure; protein structure function; receptor binding; tissue /cell culture; virus infection mechanism

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.

描述（由申请人提供）： 拟议的工作的目的是检验以下假设：与相应的单价抑制剂相比，与相应的单价抑制剂相比，二价分子 - 出现两个合适配体副本的分子将更有效的HIV -1抑制剂。特别是，我们将合成趋化因子受体CCR5的二价拮抗剂。考虑到HIV-1的高突变率，希望探索抑制HIV-1的替代策略。趋化因子受体CCR5是艾滋病治疗的特别有希望的靶标。尽管已经鉴定出通过CCR5共受体抑制HIV-1进入的分子，但设计对CCR5具有更高亲和力的抑制剂的挑战涉及比现有药物更高，并且比基于肽的治疗学更便宜，并且比基于肽的治疗学更便宜。我们已经合成了具有反应性“手柄”（游离氨基组）的已知CCR5拮抗剂的单价衍生物，并保留了抑制HIV-I抑制CCR5介导的靶细胞感染的能力。几项研究表明，二价配体比相应的单价配体更有效的几个数量级。因此，设计将同时且具有高亲和力的二价抑制剂设计二价抑制剂。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拮抗剂的两个副本通过柔性寡醇（乙二醇）接头连接。第二种策略涉及连接寡聚甘氨酸接头的CCR5拮抗剂的两个副本。这些连接器比寡醇（乙二醇）接头更刚性，并且将使我们能够确定接头对二价分子效力的柔韧性的影响。我们将测试这些抑制剂在细胞培养系统中的功效，并测试其在BALB/C小鼠中的免疫原性。对CCR5亲和力较高的二价HIV-1进入抑制剂可能在防止或延迟抗药性病毒菌株的出现方面起重要作用。这些抑制剂在靶细胞表面上二聚CCR5的能力可能会进一步增强其抑制HIV-1进入的能力。在“鸡尾酒”中使用这些有效抑制剂以及蛋白酶和逆转录酶抑制剂可能会对艾滋病治疗产生重大影响。