Carbocyclic nucleosides as therapeutics for Ebola infections

描述(申请人提供)：埃博拉病毒(EBOV)是一种A类生物恐怖主义威胁，尚不知道疫苗或小分子疗法。EBOV毒力很强，可导致高达90%的感染者死亡。由于控制EBOV所需的严格的BSL4条件，很少有人研究它们对EBOV的活性。在已研究的化合物中，一系列碳环核苷(其中天然的C-O-C键被C-C-C键取代)被证明是最有希望的起点。尤其是碳环核苷奈普诺菌素A(NPC)和3-去氮杂环普兰菌素(3-deazaNPC)在体外和体内试验中表现出良好的抗EBOV活性。这一建议的假设是，对3-deazaNPC结构的修饰，特别是杂环碱基的变化，将提供与3-deazaNPC相比具有更强的抗病毒活性和/或降低的细胞毒性的化合物。这项提议的总体目标是开发新的碳环核苷作为治疗生物恐怖威胁EBOV的药物。本建议的具体目标是优化3-deazaNPC的结构，以提高其抗EBOV的活性，并降低细胞毒性，以产生一种先进的先导化合物，从而进一步开发为治疗EBOV感染的有效药物。目前还没有治疗EBOV的特定疗法。这项建议的主要里程碑将是在感染病毒(BSL4)试验中鉴定出具有强大的(IC50=5M)抗EBOV活性和低(CC50=100M)细胞毒性的碳环核苷，这将在SBIR第二阶段拨款中进一步开发。随后的开发将理想地导致确定临床开发候选者。这项建议有以下具体目标和里程碑：与公共卫生相关：这项建议的目标是对已知的埃博拉病毒(EBOV)抑制剂3-去氮杂环素进行化学修饰，以生产具有更强抗病毒活性和/或较低细胞毒性的化合物。在有必要的情况下，将使用传统的药物化学和基于结构的药物设计来进行预期的改进。这项提议的总体目标是开发新的碳环核苷作为治疗A类生物恐怖威胁EBOV的药物。

DESCRIPTION (provided by applicant): The Ebola virus (EBOV) is a Category A bioterrorism threat for which no vaccines or small- molecule therapeutics are known. EBOV is very virulent and can cause up to 90% mortality in infected individuals. Few small molecules have been studied for their activity against EBOV, because of the stringent BSL4 conditions needed for containment of this pathogen. Of the compounds that have been investigated, a series of carbocyclic nucleosides (in which the natural C-O-C bonds are replaced by C-C-C bonds) has proven to be the most promising starting point. The carbocyclic nucleosides neplanocin A (NPC) and 3-deazaneplanocin (3- deazaNPC), in particular, demonstrated excellent activity against EBOV in in vitro and in vivo assays. The hypothesis of this proposal is that modifications to the structure of 3-deazaNPC, particularly changes in the heterocyclic base, will provide compounds with increased antiviral activity and/or reduced cytotoxicity with respect to 3-deazaNPC. The overall goal of this proposal is to develop novel carbocyclic nucleosides as therapeutics for the bioterrorist threat EBOV. The specific objective of this proposal is to optimize the structure of 3-deazaNPC to increase the antiviral activity against EBOV and reduce the cytotoxicity to produce an advanced lead compound, which can be further developed into an effective treatment for EBOV infections. No specific therapies are currently available for the treatment of EBOV. The major milestone of this proposal will be the identification of a carbocyclic nucleoside with potent (IC50 = 5 ?M) anti- EBOV activity in an infectious virus (BSL4) assay, and low (CC50 = 100 ?M) cytotoxicity, which will be further developed in a Phase II SBIR grant. Subsequent development will ideally lead to the identification of a clinical development candidate. This proposal has the following specific aims and milestones: PUBLIC HEALTH RELEVANCE: The objective of this proposal is to chemically modify the known Ebola virus (EBOV) inhibitor 3- deazaneplanocin to produce compounds with greater antiviral activity and/or lower cytotoxicity. Traditional medicinal chemistry and structure-based drug design will be used, where warranted, to make the desired improvements. The overall goal of this proposal is to develop novel carbocyclic nucleosides as therapeutics for the Category A bioterrorist threat EBOV.