Carbocyclic nucleosides as therapeutics for Ebola infections

描述（由申请人提供）：埃博拉病毒（EBOV）是A类生物恐怖主义威胁，目前还没有疫苗或小分子治疗剂。EBOV是非常致命的，可导致感染个体高达90%的死亡率。很少有小分子被研究其对EBOV的活性，因为遏制这种病原体需要严格的BSL 4条件。在已研究的化合物中，一系列碳环核苷（其中天然C-O-C键被C-C-C键取代）已被证明是最有希望的起点。特别地，碳环核苷奈普拉诺菌素A（NPC）和3-脱氮奈普拉诺菌素（3- deazaNPC）在体外和体内测定中表现出针对EBOV的优异活性。该提议的假设是，对3-脱氮NPC的结构的修饰，特别是杂环碱基的改变，将提供相对于3-脱氮NPC具有增加的抗病毒活性和/或降低的细胞毒性的化合物。该提案的总体目标是开发新型碳环核苷作为生物恐怖主义威胁EBOV的治疗剂。该提案的具体目标是优化3-deazaNPC的结构，以增加针对EBOV的抗病毒活性并降低细胞毒性，从而产生先进的先导化合物，其可以进一步开发为EBOV感染的有效治疗。目前没有特定的疗法可用于治疗EBOV。该提案的主要里程碑将是鉴定具有强效（IC 50 = 5？M）在感染性病毒（BSL 4）测定中的抗EBOV活性，和低（CC 50 = 100？M）细胞毒性，这将在第二阶段SBIR赠款中进一步开发。理想情况下，后续开发将导致临床开发候选产品的识别。该提案具有以下具体目标和里程碑：公共卫生相关性：该提案的目的是对已知的埃博拉病毒（EBOV）抑制剂3- deazaneplanocin进行化学修饰，以产生具有更高抗病毒活性和/或更低细胞毒性的化合物。在必要的情况下，将使用传统的药物化学和基于结构的药物设计来进行所需的改进。该提案的总体目标是开发新型碳环核苷作为A类生物恐怖主义威胁EBOV的治疗剂。

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.