Our research group will work at the interface of chemistry and biology by solving biological problems with chemical means.
1.Chemical Stabilization of Peptide Secondary Structure and Its Biological Fuctionality
Protein-protein interactions (PPIs) play a crucial role in most cellular signaling events, therefore are considered as potential therapeutic targets. However, most PPIs usually have larger contact surface area than that of G-protein-coupled receptors or protein kinases described as “druggable” targets. Therefore, developing molecular mimicry of chemically stabilized protein secondary structures remains an active area in this research field to achieve clinically-relevant therapeutic agents. Artificially mimic α-helical short peptides by chemically introduction of “stapling” amino acids at the primary sequence level with covalent macrocycles become increasingly intriguing.
2.Modulation of Microbial Virulence and Research on Anti-Infection Treatment
SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatase (Stk1/Stp1) were found to modulate phosphorylation of SarA/MgrA family regulators as well as staphylococcal virulence. Importantly, stp1-deficient strain shows significant virulence reduction in mice, implying Stp1 as an alternative drug target. Our lab found that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in vivo. MDSA inhibits Stp1 more potently over commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to a new approach for combating staphylococcal infection by targeting Stp1.