Carbocyclic nucleosides as therapeutics for Ebola infections

描述（由申请人提供）：埃博拉病毒（EBOV）是一种a类生物恐怖主义威胁，目前还没有已知的疫苗或小分子疗法。EBOV毒性很强，可导致感染者高达90%的死亡率。由于遏制这种病原体需要严格的BSL4条件，因此很少有小分子研究其对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）已被证明是最有希望的起点。特别是碳环核苷neplanocin A （NPC）和3- deazaNPC (3- deazaNPC)，在体外和体内实验中显示出良好的抗EBOV活性。该提议的假设是，对3-deazaNPC结构的修改，特别是杂环基的改变，将使化合物具有更高的抗病毒活性和/或降低3-deazaNPC的细胞毒性。本提案的总体目标是开发新型碳环核苷作为生物恐怖威胁EBOV的治疗药物。本课题的具体目标是优化3-deazaNPC的结构，提高其对EBOV的抗病毒活性，降低细胞毒性，制备高级先导化合物，进一步开发成为治疗EBOV感染的有效药物。目前尚无治疗EBOV的特异性疗法。该提案的主要里程碑将是鉴定出一种有效的(IC50 = 5 ？M)在感染性病毒（BSL4）试验中抗EBOV活性低(CC50 = 100 ？M)细胞毒性，将在II期SBIR拨款中进一步发展。理想情况下，后续开发将导致临床开发候选药物的确定。公共卫生相关性：本提案的目标是化学修饰已知的埃博拉病毒（EBOV）抑制剂3-地氮烷planocin，以产生具有更强抗病毒活性和/或更低细胞毒性的化合物。传统的药物化学和基于结构的药物设计将被使用，在必要的情况下，做出期望的改进。本提案的总体目标是开发新型碳环核苷作为A类生物恐怖威胁EBOV的治疗药物。

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.