ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) has been identified to be a mutation hot spot, with the P323L mutation being commonly observed in viral genomes isolated from North America. RdRp forms a complex with nonstructural proteins nsp7 and nsp8 to form the minimal replication/transcription machinery required for genome replication. As mutations in RdRp may affect formation of the RdRp-nsp7-nsp8 supercomplex, we analyzed viral genomes to identify mutations in nsp7 and nsp8 protein sequences. Based on in silico analysis of predicted structures of the supercomplex comprising of native and mutated proteins, we demonstrate that specific mutations in nsp7 and nsp8 proteins may have a role in stabilization of the replication/transcription complex.
Subject(s)
Coronavirus RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2/physiology , Viral Nonstructural Proteins/genetics , Viral Replication Compartments/chemistry , Amino Acid Sequence , Computer Simulation , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Genome, Viral , Humans , Models, Molecular , Mutation , Protein Stability , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Replication Compartments/metabolismABSTRACT
The SARS-CoV-2 pandemic, declared as a global health emergency by the WHO in February 2020, has currently infected more than 6 million people with fatalities near 371,000 and increasing exponentially, in absence of vaccines and drugs. The pathogenesis of SARS-CoV-2 is still being elucidated. Identifying potential targets and repurposing drugs as therapeutic options is the need of the hour. In this review, we focus on potential druggable targets and suitable therapeutics, currently being explored in clinical trials, to treat SARS-CoV-2 infection. A brief understanding of the complex interactions of both viral as well as host targets, and the possible repurposed drug candidates are described with an emphasis on understanding the mechanisms at the molecular level.