Novel Therapeutic Peptides
Cyclic peptides have many properties that make them ideal for use as therapeutics. Desirable properties of cyclic peptides include, for example, high target affinity and selectivity, and low toxicity. A common feature of many cyclic peptides that have been isolated from natural sources, such as bacteria and fungi, is the presence of one or more unnatural amino acids. These unnatural amino acids improve the peptide's ability to resist proteolytic degradation, and provide unique chemical and structural motifs that can greatly improve the binding properties of the peptide. Our lab is developing technology to produce libraries of cyclic peptides containing diverse unnatural amino acids. These libraries can be used to rapidly identify novel cyclic peptides that bind to diverse drug targets. Our primary interest is in identifying cyclic peptides with anticancer and antiviral properties.
Engineered Suppressor tRNAs
The genetic code is comprised of 64 codons. These include 61 amino-acid-encoding codons, and three “stop codons”. Instead of coding for an amino acid, stop codons tell the ribosome to terminate protein synthesis. Approximately 10–15% of genetic diseases are caused by mutations that convert amino-acid-encoding codons into stop codons (1). These mutations introduce premature stop codons (PSCs) into protein-coding genes, causing protein synthesis to terminate prematurely. Our lab is working to engineer novel suppressor tRNAs—tRNAs that prevent PSCs from terminating protein synthesis. These suppressor tRNAs have the potential to treat debilitating diseases that are caused by PSCs, such as cystic fibrosis and Duchenne muscular dystrophy.
Genetic Code Reprogramming
In nature, proteins are made using only 22 different amino acids that have relatively limited chemical and structural diversity. However, by engineering the protein synthesis machinery of cells, methods have been developed to install diverse unnatural amino acids into proteins. The ability to install unnatural amino acids into proteins in living cells has revolutionized the field of protein chemistry. Several projects have been initiated in our lab with a focus on expanding the utility of genetic code reprogramming. These include: (1) engineering aminoacyl-tRNA synthetases to recognize new unnatural amino acids with useful properties, and (2) developing platforms to install multiple distinct unnatural amino acids into proteins. Using these tools we have the ability to probe complex biological systems with unprecedented precision.