Computation and Repurposing to identfy antivirals directed against dominant

抗药性病毒的快速进化是治疗RNA病毒感染的有效化合物如此之少的唯一最大原因。已经寻求了几种方法来规避耐药的高频率。以宿主因素为目标是本联合体中的几项提案所代表的一项出色的战略。多种药物疗法正在成功地用于治疗艾滋病毒感染，但显然需要多种药物的存在。我们正在开发一种新的范式，以开发“主要药物靶点”的抑制剂：当药物结合时，这些病毒产物主要干扰同一细胞内耐药产物的生长。这里的前提是，耐药病毒总是会被制造出来，但有可能通过靶向寡聚蛋白来减轻它们的选择压力，寡聚蛋白将是耐药亚单位和药物敏感亚单位的嵌合混合物。为此，我们确定了五个潜在的主导药物靶点，重点放在基于结构的建模上。这些高度寡聚的靶点是丙型肝炎病毒和登革病毒的核心蛋白结构，二十面体对称的登革病毒包膜，以及甲型肝炎和肠道病毒71型的衣壳结构。对于每个建模项目，一种独特的方法将是使用一个经过严格管理的已知或批准药物的数据库，称为WONTKILL(无毒药物、ILLICAL和法律的世界)。最近对该数据库进行了挖掘，以确定目前正在进行的克氏锥虫感染临床试验中的一种用途改变的化合物。潘德实验室开发的创新采矿技术包括分子相似性和快速化学信息学方法。选定的潜在化合物将被评估在抑制病毒生长方面的有效性，以及同样重要的是，在组织培养和小鼠模型中出现耐药性的频率。这些实验的成功完成将产生新的或更好的重新定位的化合物，这些化合物既能抑制靶RNA病毒，又能降低因出现耐药性而变得毫无用处的风险。

The rapid evolution of drug-resistant viruses is the single greatest reason that there are so few effective compounds available to treat RNA viral infections. Several approaches to circumvent the high frequencies of drug resistance have been pursued. Targeting host factors is an excellent strategy represented by several proposals in the present consortium. Multi-drug therapy is being used successfully to treat HIV infections, but obviously requires the existence of multiple drugs. We are developing a new paradigm, to develop inhibitors of 'dominant drug targets': those viral products that, when drug-bound, dominantly interfere with the growth of drug-resistant products within the same cell. The premise here is that drug-resistant viruses will always be made, but that it is possible to blunt the selection pressure on them by targeting oligomeric proteins that will be chimeric mixtures of drug-resistant and drug-susceptible subunits. To this end, we have identified five potential dominant drug targets on which to focus structure-based modeling. These highly oligomeric targets are the core protein structures of HCV and Dengue viruses, the icosahedrally symmetric Dengue virus envelope and the capsid structures of hepatitis A and enterovirus 71. For each modeling project, a unique approache will be the use of a heavily curated data base of known or approved drugs, termed WONTKILL (World of Non-Toxic Khemicals, ILIegal and Legal). This database has recently been mined to identify a repurposed compound currently in clinical trials for Trypanosma cruzi infections. Innovative mining techniques developed in the Pande laboratory include molecular similarity and rapid cheminformatics approaches. Selected potential compounds will be evaluated for efficacy in inhibiting viral growth and, just as importantly, the frequency of emergence of drug resistance in tissue culture and mouse models. Successful completion of these experiments will yield novel or, even better, repurposed compounds that both inhibit the target RNA viruses and display lowered risk of being rendered useless by the emergence of drug resistance.