Anti-HSP90 monoclonal antibody, clone 5G4.F9

Murine norovirus (MNV), is a prevalent pathogen of laboratory mice closely related to human norovirus (HuNoV), a contagious pathogen known to cause gastroenteritis worldwide; however, the mechanism of norovirus replication remains poorly understood. Both heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp70) play an important role in viral genome replication and viral gene expression. In this study, we first found that heat stress exerted a positive effect on the replication of MNV in the murine macrophage RAW264.7 cell line. Inhibition of Hsp70 and Hsp90 by the specific inhibitors, KNK437 and 17-AGG, respectively showed that Hsp70 and Hsp90 enhanced MNV genome replication and virion production. In addition, we found that KNK437 and 17-AGG could decrease the level of IL-1 beta, IL-10, and TNF-alpha mRNA expression in MNV-infected cells. These data suggested that heat stress can positively regulate MNV replication, which advances our understanding of the molecular mechanism of MNV infection.

Due to the contribution of drug-target binding kinetics to drug efficacy, there is a high level of interest in developing methods to predict drug-target binding kinetic parameters. During the review period, a wide range of enhanced sampling molecular dynamics simulation-based methods has been developed for computing drug-target binding kinetics and studying binding and unbinding mechanisms. Here, we assess the performance of these methods considering two benchmark systems in detail: mutant T4 lysozyme-ligand complexes and a large set of N-HSP90-inhibitor complexes. The results indicate that some of the simulation methods can already be usefully applied in drug discovery or lead optimization programs but that further studies on more high-quality experimental benchmark datasets are necessary to improve and validate computational methods.