Iowa State University
Thioimidates: An Obscure Functional Group Provides General Access to Peptide Bond Isosteres
SESSION 4: PROTEIN ARCHITECTURES - STRUCTURE AND FUNCTION
Monday, June 26, 2023, at 09:20 am - 09:40 am
The prevalence of post-translational modification in nature suggests that expanding beyond the suite of functional groups found in the 20 canonical amino acids can impart specialized utility to peptide-based biomolecules. Thioamides and amidines are two such modifications that can act as peptide bond isosteres with unique properties. Amidines, in particular, have received considerably little attention in peptides due to limitations in methods to access them. We developed the first robust and general procedure for the introduction of amidines into peptide backbones.
We exploited the utility of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. We also further demonstrate how thioimidate protecting groups can address many of the problematic synthetic issues surrounding thioamide backbone modifications as well.
This work is significant because it describes a generally applicable path to access unexplored peptide designs and architectures for new therapeutics made possible by the unique properties of thioamides and amidines.
Brett was born in Ontario, Canada and received his B.Sc. in chemistry from McMaster University in 2006. During his time at McMaster, he performed undergraduate research with Professor Mónica Barra at the University of Waterloo and with Professor Alex Adronov at McMaster University. He began his graduate studies with Professor Timothy M. Swager at the Massachusetts Institute of Technology in 2006 as an NSERC graduate fellow. At MIT he developed new syntheses of conjugated polymers for applications in biosensing and conductive materials.
After receiving his Ph.D. in 2011, he moved to the University of Wisconsin–Madison as a Canadian Institutes of Health Research Postdoctoral Fellow working with Professor Ronald T. Raines. At UW–Madison he studied secondary molecular orbital interactions that contribute to the stability of proteins, as well as boronic acids and thiol reducing agents for protein chemistry applications. Brett joined the faculty at Iowa State University in August 2014 as an Assistant Professor and was promoted to Associate Professor in 2020.