Computation and Repurposing to identfy antivirals directed against dominant

计算和重新利用以确定针对显性病毒的抗病毒药物

基本信息

批准号：
8643867
负责人：
VIJAY S PANDE
金额：
$ 71.76万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643867
关键词：
Antiviral Agents Binding Capsid Cells Chagas Disease Chemicals Clinic Clinical Trials Complex Computing Methodologies Core Protein Databases Dengue Dengue Virus Development Docking Drug Targeting Drug resistance Effectiveness Enterovirus 71 Evolution Frequencies Genome Growth HIV HIV Infections Hepatitis A Hepatitis A Virus Hepatitis C Hepatitis C virus Homo Homology Modeling Human Human poliovirus Hybrids Infection Integration Host Factors Laboratories Lead Legal Ligands Malaria Mining Modeling Molecular Mutation Outcome Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Polioviruses Population Proteins RNA RNA Viruses Resistance Risk Scheme Structure Techniques Testing Viral Viral Proteins Virus Virus Diseases base cheminformatics drug resistant virus env Gene Products genetic analysis improved inhibitor/antagonist innovation loss of function monomer mouse model novel pharmacophore pressure protein protein interaction protein structure research study small molecule success theories tissue culture virus envelope

项目摘要

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.

抗药性病毒的快速演变是最大的原因，即有效的化合物可用于治疗RNA病毒感染。已经采用了几种规避高频率耐药性的方法。靶向寄主因素是当前财团中几个建议所代表的一个极好的策略。多药疗法已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“主要药物靶标”的抑制剂：当药物结合时，这些病毒产物主要干扰同一细胞中耐药产品的生长。这里的前提是始终将抗药性病毒生成，但是可以通过靶向将是耐药和耐药亚基的嵌合混合物来靶向对它们的选择压力。为此，我们已经确定了五个潜在的主导药物靶标，以聚焦基于结构的建模。 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和法律）。该数据库最近已被开采，以识别当前在锥虫Cruzi感染的临床试验中的重新利用化合物。在Pande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。将评估选定的潜在化合物在抑制病毒生长方面的功效，同样重要的是，在组织培养和小鼠模型中耐药性出现的频率。这些实验的成功完成将产生新颖的，甚至更好，甚至更好地重新利用的化合物，既抑制靶RNA病毒又显示出耐药性出现使其无用的风险降低。