Hsa-miRNA-23a-3p promotes atherogenesis in a novel mouse model of atherosclerosis.

Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in LDLRW483X in C57BL/6 mice, as the W483X mutation in LDLR is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 (TNFAIP3) gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting TNFAIP3 through the NF-κB and p38/MAPK signaling pathways.

Identification, synthesis and pharmacological evaluation of novel anti-EV71 agents via cyclophilin A inhibition.

In this work, the relationship between cyclophilin A (CypA) and EV71 prompted us to screen a series of small molecular CypA inhibitors which were previously reported by our group. Among them, compounds 1 and 2 were discovered as non-immunosuppressive anti-EV71 agents with an EC50 values of 1.07±0.17µM and 3.36±0.45µM in virus assay, respectively, which were desirably for the further study. The subsequent chemical modifications derived a novel class of molecules, among which compound 11 demonstrated the most potent anti-EV71 activity in virus assay (EC50=0.37±0.17µM), and low cytotoxicity (CC50>25µM). The following CypA enzyme inhibition studies indicated that there was not only the enzyme inhibition activity, undoubtedly important, functioning in the antiviral process, but also some unknown mechanisms worked in combination, and the further study is underway in our laboratory. Nevertheless, to the best of our knowledge, compound 11 was probably the most potent small molecular anti-EV71 agent via CypA inhibitory mechanism to date. Consequently, our study provided a new potential small molecule for curing EV71 infection.

Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization.

In this work, the relationship between cyclophilin A (CypA) and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non-immunosuppressive anti-HCV agent with an EC50 value of 0.67 µM in a virus assay, was selected for further study. Subsequent chemical modification by O-acylation led to a novel class of molecules, among which compound 25 demonstrated the most potent anti-HCV activity in the virus assay (EC50 = 0.19 µM), but low cytotoxicity and hERG cardiac toxicity. The following studies (a solution stability assay and a simple pharmacokinetic test together with a CypA enzyme inhibition assay) preliminarily indicated that 25 was a prodrug of 1. To the best of our knowledge, 25 is probably the most potent currently reported small molecule anti-HCV agent acting via the CypA inhibitory mechanism. Consequently, our study has provided a new potential small molecule for curing HCV infection.