Novel Therapeutic Strategies Targeting Re-emerging Alphaviruses

我们项目(3)的主要目标是开发针对甲病毒的新型核苷和核苷酸抑制剂。开发针对这些重要人类病原体的治疗方法是非常重要的。我们建议通过使用吉利德化学文库（5万个杂环和核苷类似物）、Tranzyme的HitCreate文库（5万个宏环）和Diversity文库（2.7万个杂环）进行高通量筛选来鉴定CHIKV和VEEV复制的有效抑制剂。对这两种病毒显示活性的化合物将进一步验证，然后对其在甲病毒属中的特异性、在多种相关细胞类型中的功效和毒性、作用模式和病毒突变体的产生进行表征。通过第二组过滤器的化合物将进行Hit以进行优化和SAR，随后在第二筛中进行重新测试。最后，我们将在相关小鼠和非人灵长类动物模型上对具有良好生物利用度和活性的化合物进行甲病毒感染和疾病的体内功效测试。通过这些研究，我们将开发针对多种甲病毒属成员的强效抗病毒药物。

The main goal of our Project (3) is to develop novel nucleoside and nucleotide inhibitors directed against Alphaviruses. There is a very important need for the development of treatments against these important human pathogens. We propose to identify potent inhibitors of CHIKV and VEEV replication by performing a high-throughput screen with chemical libraries from Gilead (50,000 heterocycles and nucleoside analogs), HitCreate library from Tranzyme (50,000 macrocycles) and the Diversity Library (27,000 heterocycles). Compounds displaying activity against the two viruses will be further validated and then characterized for specificity within the Alphavirus genus, efficacy and toxicity in multiple relevant cell-types, mode of action, and generation of viral mutants. Compounds that pass this second set of filters will undergo Hit to lead optimization and SAR with subsequent retesting in secondary screens. Last of all, we will perform in vivo efficacy testing in relevant mouse and non-human primate models of alphavirus infection and disease for compounds with good bioavailability and activity. Through these studies we will develop robust antiviral agents against multiple members of the Alphavirus genus.