Variation Analysis of SARS-CoV-2 Omicron RdRp and Construction of its Active Reaction System
RNA-dependent RNA polymerase(RdRp)is the main antiviral target due to its crucial role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)replication.The function of RdRp is strictly dependent on its spatial structure.Since mu-tations in key amino acid sites may lead to changes in spatial structure and function,it is necessary to investigate whether the RdRp inhibitor effective on SARS-CoV-2 prototype strain still has inhibitory effect on Omicron variants.Then 913 RdRp high-quality sequences of Omicron variants prevalent in China in the past two years were analyzed by multiple sequence alignment.Compared with the prototype strain,these Omicron variants had both synonym and missense mutations.Among the missense mu-tations,with the exception of a few low-frequency mutation sites,44%had P323L single mutation,34%had P323L and G671S dual mutation,and 12%had P323L,G671S and D63N triple mutation.The Omicron RdRp sequences containing these three types of mutations were respectively grouped as 1_RdRp,2_RdRp and 3_RdRp.AlphaFold2 was used to construct the protein structure model of these three types of RdRp,and PyMOL was used to superposition the RdRp structure of Omicron and the pro-totype strain.The results showed that all the three protein structure models could be highly superimposed with the RdRp of the prototype(6M71_RdRp),suggesting that these mutations did not alter the spatial structure of RdRp.Further,three Omicron RdRp protein models were respectively docked with four reported RdRp inhibitors,and the results showed that these four inhibi-tors could still stably bind to the active center of each Omicron RdRp model,suggesting that RdRp is a long-term effective target.Based on this,an extracellular RdRp enzymatic reaction and detection system was constructed,which would be helpful for the evaluation or screening of antiviral drugs targeting RdRp.
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