Our research interfaces organic chemistry and membrane biology. As chemists, we are fascinated by the exquisite selectivity that biomolecules exhibit for their intended partners. Programmed molecular interactions as such underlie essentially all aspects of biology. Specifically, our group has been studying important bacterial lipids and how their interaction with other molecules contributes to bacterial virulence and antibiotic resistance. We approach this problem by creating synthetic molecules that can target the lipid of interest with protein-like specificity. Synthetic molecules as such may find use as imaging contrast agents and as powerful antibiotics. Shown below are two related projects ongoing in our lab.
1. Synthetic receptors for membrane lipids
To recognize specific membrane lipids, nature has evolved a number of large proteins that display well-crafted pockets for substrate binding. However, these lipid-binding proteins are less ideal to serve as imaging probes or as therapeutics due to their large size and difficulty to express and label. Inspired by peptide natural products like vancomycin and nisin, which are known to bind lipid substrates with high affinity and selectivity, we have been developing synthetic peptides as low-molecular-weight receptors for membrane lipids. Toward this goal, we devise novel designs of conformationally rigidified peptides and examine their potential to target biologically important lipids. For example, synthetic receptors of bacterial lipids may serve as powerful antibiotics, similar to vancomycin and nisin.
Substructure of vancomysin (yellow) binding to lipid II fragment (cyan)
2. Novel mechanisms to achieve specific molecular recognition
Nature primarily relies on canonical noncovalent interactions, including hydrogen bonding and salt bridge formation, to direct a molecule to bind its cognate partner. Synthetic probes and therapeutics, however, are not limited to these mechanisms to bind their targets. We have been examining novel mechanisms of molecular interaction that can be added into the toolbox of chemists for designing probes and therapeutics. For example, we have shown that fluorinated aromatic amino acids can elicit selective binding to their natural counterparts through pi-pi stacking. More recently, we have demonstrated the use of reversible covalent bond formation to target amine-presenting lipids. Complementing hydrogen bonds and salt bridges, these novel mechanisms are expected to greatly facilitate the development of probes and inhibitors of important biomolecules.
Pi-pi stacking leads to specific protein dimerization