HSP70 positively regulates translation by interacting with the IRES and stabilizes the viral structural proteins VP1 and VP3 to facilitate duck hepatitis A virus type 1 replication.

The maintenance of viral protein homeostasis depends on the interaction between host cell proteins and viral proteins. As a molecular chaperone, heat shock protein 70 (HSP70) has been shown to play an important role in viral infection. Our results showed that HSP70 can affect translation, replication, assembly, and release during the life cycle of duck hepatitis A virus type 1 (DHAV-1). We demonstrated that HSP70 can regulate viral translation by interacting with the DHAV-1 internal ribosome entry site (IRES). In addition, HSP70 interacts with the viral capsid proteins VP1 and VP3 and promotes their stability by inhibiting proteasomal degradation, thereby facilitating the assembly of DHAV-1 virions. This study demonstrates the specific role of HSP70 in regulating DHAV-1 replication, which are helpful for understanding the pathogenesis of DHAV-1 infection and provide additional information about the role of HSP70 in infection by different kinds of picornaviruses, as well as the interaction between picornaviruses and host cells.

Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2.

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.

Discovery of a novel Pleuromutilin derivative as anti-IPF lead compound via high-throughput assay.

Idiopathic pulmonary fibrosis (IPF) is a highly fatal disease that lacks appropriate treatments and highly effective drugs. Many reported indicated that the TGF-ß1/Smad3 signaling pathway played a pivotal role in development of IPF. In this case, it was hypothesized that discovery novel compounds to block the TGF-ß1/Smad3 signaling pathway might be useful for treatment of IPF. Therefore, a high-throughput screening system based on stably transfected CAGA-NIH3T3 cells was established for discovering lead compounds which could validly suppress the TGF-ß1/Smad3 signal path. In this study, a series of novel Pleuromutilin derivatives were prepared and quickly evaluated by high-throughput assay. The lead compound 32 was discovered to be able to remarkably suppress the TGF-ß1/Smad3 pathway in vitro. Further biological evaluation revealed that compound 32 could remarkably decrease the myofibroblast stimulation and extracellular matrix (ECM) deposition. More importantly, compound 32 could remarkably mitigate bleomycin (BLM)-triggered lung fibrosis in mice models. Additionally, the lead compound possess excellent pharmacokinetics properties, good oral availability and low toxicity. In general, our study has demonstrated the potency of a novel Pleuromutilin derivative (compound 32), which might be a prospective candidate for developing anti-IPF medicines by suppress the TGF-ß1/Smad3 signal pathway.