Conserved allosteric inhibitory site on the respiratory syncytial virus and human metapneumovirus RNA-dependent RNA polymerases

Respiratory syncytial virus (RSV) and Human metapneumovirus (HMPV) are two of the most common causes of respiratory infections in children, elderly, and immunocompromised people worldwide. Inhibitors for viral replication using small molecule inhibitors are being developed, but the binding location and molecular process of this inhibitors are still largely understood. This study analyzed the interaction between the RSV and HMPV polymerases and MRK-1, a non-nucleoside pneumovirus inhibitor. According to a functional analysis of the RSV polymerase in the presence of MRK-1, the molecule inhibits both initiation and early elongation, indicating that it works as an allosteric inhibitor to stop the conformational changes that the polymerase experiences in the early stages of RNA synthesis. According to the Northern blot analysis of minigenome-generated RNAs, the increase in MRK-1 concentration decreased both mRNA and antigenome accumulation, indicating that the ligand suppresses the function of both processes. The results presented in this study provide beneficial information on the structure-function characteristics of the polymerases of RSV and HMPV and the insight into the interaction of a small molecule inhibitors that targets them. 

(MA)