University of Wyoming
Talk Session: SESSION 9: INNOVATIONS IN PEPTIDE AND PROTEIN CHEMISTRY
Date: Tuesday, June 14, 2022
Talk Time: 12:20 pm - 12:40 pm
Talk Title: Optically Controlled Protein Modification Chemistry
Michael grew up in Salisbury, on the eastern shore of Maryland, and received his undergraduate degree from Salisbury University in 2006. There, he was an undergraduate researcher in Professor Elizabeth Papish’s group where he worked on the synthesis of small molecule-metal complexes designed to mimic metalloenzyme active sites. He then moved to the University of Delaware, where he pursued his Ph.D. in Professor Joseph Fox's laboratory. His research in the Fox group focused on the development of new synthetic methods, the total synthesis of natural products, and the development of bio-orthogonal chemistry.
After receiving his Ph.D. in Organic Chemistry in 2013, he moved to the United Kingdom to take up a post-doctoral position in the laboratory of Professor Matthew Gaunt at the University of Cambridge, where he was awarded a Marie Curie Postdoctoral Fellowship in 2014. His research at Cambridge primarily focused on the development of a non-classical reactive platform for the selective chemical modification of proteins. In August of 2017, Michael moved back across the pond to take up his position in the Chemistry Department at the University of Wyoming.
By virtue of the notion that all life on earth is organic and is therefore controlled by the chemistry of organic molecules, the study of synthetic organic chemistry is fundamentally linked to an understanding of life. Through this relationship, synthetic organic chemists play an integral role in the improvement of human health. Moreover, our unique ability to design functional molecules for various purposes allows us to facilitate discoveries in other fields of science related to human health such as medicine, biology and materials science. Organic chemists enable discovery.
With this backdrop as inspiration, the Taylor group’s research program is underpinned by a focus towards basic research in organic chemistry at the interface with biology and medicine. Our goal is to use our expertise in reaction design to address fundamental challenges in this area, and then seek to apply our solutions in a translational sense through establishing productive collaborations. Three distinct interests are: 1 new methods for the chemical modification of biomolecules2 organic reaction design for in situ generation of therapeutic compounds, and 3 new organocatalytic strategies for the synthesis of high value chemicals.
Biocompatible chemical transformations that are promoted by light have become powerful tools in chemical biology by virtue of enabling spatiotemporal control over activity. Whilst genetically encoded, photoactivatable tools have become mainstays in bio-orthogonal chemistry, photochemistries that covalently label native biomolecular structures, photobioconjugation, that are also biocompatible are comparatively limited.
We recently reported an approach to protein photo-bioconjugation process that exploits the inherent photo- and redox-lability of Tryptophan, Trp, residues by pairing a Trp residue with an N-carbamoyl pyridinium salt that simultaneously couples photo-induced electron transfer, PET, with Trp to a radical fragmentation/recombination process to carbamylate Trp residues site-selectively with high efficiency. By invoking this unusual reaction mechanism, we are able to access chemical modifications on traditionally non-reactive biological moieties, namely Trp residues, with rapid kinetics and under biologically compatible conditions.
Our studies to date have revealed that the pyridinium scaffold provides robust, optically triggered protein labelling in applications for protein conjugate synthesis as well as for intracellular chemoproteomic profiling of Trp residues.
Moreover, we have shown that the pyridinium scaffold is highly tunable; enabling precision control over photophysical and electrochemical properties. We have exploited this tunability to design pyridinium reagents that label Trp residues both by differing reaction mechanisms and at differing optical triggering windows. This, in turn, allows us to couple reaction mechanism to wavelength; enabling optical control over labelling chemistry.
We anticipate that this ability will enable the design of reagents and experimental workflows of increasing sophistication and capabilities.