RAPID: Impact of inhibitors on SARS-CoV-2 polymerase and fidelity control of RNA synthesis

RNA依赖的RNA聚合酶(RdRp)是SARS-CoV、MERS-CoV等RNA病毒复制和转录的核心酶。研究RdRp的作用机制为开发新的抗病毒药物和了解耐药现象的出现提供了希望，这对于有效应对由SARS-CoV-2引起的新冠肺炎危机至关重要。这个项目将使用分子建模来研究RdRp功能背后的结构动力学。值得注意的是，Remdesivir是一种核苷酸类似物，将被用来询问RdRp的保真度，并更好地了解它如何促进病毒进化，以及这种药物抗病毒活性的基础。该项目还为研究生和本科生提供了计算生物学方面的培训机会。计划对保守的SARS-CoV RdRp酶进行分子建模和全原子分子动力学模拟，以研究控制核苷酸加成循环和复制保真度的结构动力学和能量学。该项目是由特定问题指导的，包括核苷酸类似物如何影响RdRp对正确核苷酸的选择，非核苷酸抑制剂如何影响RdRp机制，以及RdRp的哪些突变可能导致耐药性。这些结果有望为治疗干预提供关于这种重要靶标酶的新的机制信息。这一快速奖项是由分子和细胞生物科学部门的遗传机制计划利用冠状病毒援助、救济和经济安全(CARE)法案的资金做出的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

RNA-dependent RNA polymerase (RdRp) is the core enzyme responsible for replication and transcription in RNA viruses such as SARS-CoV and MERS-CoV. Investigating the mechanism of action of RdRp offers promise for development of new antiviral therapeutics and for understanding the emergence of drug resistance, which is critical for an effective response to the COVID-19 crisis caused by SARS-CoV-2. This project will employ molecular modeling to investigate the structural dynamics underlying RdRp function. Notably, Remdesivir, a nucleotide analog, will be utilized to interrogate RdRp fidelity and better understand how it contributes to viral evolution, as well as the basis for the antiviral activity of this drug. The project also offers training opportunities for graduate and undergraduate students in computational biology.Molecular modeling and all-atom molecular dynamics simulations of conserved SARS-CoV RdRp enzymes are planned to investigate the structural dynamics and energetics governing the nucleotide addition cycle and replication fidelity. The project is guided by specific questions, including how nucleotide analogs impact selection of the correct nucleotide by RdRp, how non-nucleotide inhibitors affect the RdRp mechanism, and what mutations in RdRp might enable drug resistance. The outcomes are expected to yield novel mechanistic information about this important target enzyme for therapeutic intervention. This RAPID award is made by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.