Discovery and Advancement of Chikungunya virus inhibitors

 描述(由申请人提供)：迫切需要新的基孔肯雅病毒(CHIKV)抑制剂来应对这种病原体在美洲令人震惊的传播。这项第一阶段SBIR可行性研究的目标是确定最多3个能够特异性和选择性地抑制细胞培养中CHIKV复制的类药物化合物铅系列。为此，我们 已经开发并验证了一种高通量筛选试验，适用于在细胞培养中对活性CHIKV复制进行化合物筛选。我们将对100,000多种具有最佳类药物特性的化合物库进行高通量的抗CHIKV筛选活动。从这一活动中产生的高质量的打击将被描述为效力、选择性、针对CHIKV和相关甲型病毒的活性光谱以及作用机制。该系列化合物中最有趣的将通过药物化学来探索结构-活性关系(SAR)。将对每个系列中具有代表性的化合物的口服生物利用度进行早期评估。成功将触发第二阶段SBIR拨款的提交，该拨款将推动该系列的化学优化为“预开发的候选选择”。第二阶段将包括在UTMB的Weaver博士的实验室对CHIKV疾病动物模型进行概念验证测试。这里描述的工作有望导致识别一个或多个急需的针对基孔肯雅病毒的抑制剂系列。

 DESCRIPTION (provided by applicant): Novel inhibitors of Chikungunya virus (CHIKV) are urgently needed to address the alarming spread of this pathogen across the Americas. The objective of this Phase I SBIR feasibility study is to identify up to 3 drug-like compound lead series that specifically and selectively inhibit CHIKV replication in cell culture. To this end, we have developed and validated a high-throughput screening assay that is suitable for compound screening against active CHIKV replication in cell culture. We will conduct a high-throughput anti-CHIKV screening campaign of a library of over 100,000 compounds with optimal drug-like properties. Quality hits that emerge from this campaign will be profiled for potency, selectivity, spectrum of activity against CHIKV and related alphaviruses, and mechanism of action. The most interesting of the compound series will undergo medicinal chemistry hit-to-lead efforts to explore structure-activity relationships (SAR). Early assessment of the oral bioavailable of representative compounds from each series will be undertaken. Success will trigger the submission of a Phase II SBIR grant that will drive chemical optimization of the series to "Candidate Selection for Pre-development". Phase II will include Proof of Concept testing in animal models of CHIKV disease in the laboratory of Dr. Weaver at UTMB. The work described herein is expected to lead to the identification of one or more urgently needed inhibitor series that target Chikungunya virus.