We have developed a robust approach for the introduction of diyne linkers into peptides using ligand optimization to promote the Glaser reaction. The resulting rigid, linear 7 Å linkage is highly effective for linking macromolecules. In addition, when performed in an intramolecular context, diyne linkers can be utilized as tethers or stables to stabilize alpha helical structures. Further, we find that this approach can facilitate the formation of strained macrocycles that promote the full extension / exposure of the polypeptide backbone. The utility of these highly constrained macrocycles to mimic more complex natural products will be discussed.
Philip Dawson is a Professor of Chemistry at The Scripps Research Institute (TSRI) in La Jolla, CA and the Dean of Graduate and Postdoctoral Studies. He received an A.B. in Chemistry from Washington University in St. Louis (1992) and a Ph.D. from TRSI (1996). After pursuing postdoctoral work at the California Institute of Technology, he joined the TSRI faculty in 1997. In 2011, Dr. Dawson joined the Dean’s Advisory Committee and, in 2012, became Associate Dean of Graduate Studies. In 2017, Dr. Dawson became Dean of Graduate and Postdoctoral Studies. He has been a member of the council of the American Peptide Society since 2007 as councilor (2007-2013) and as President Elect (2013-15) and President (2015-17).
Dr. Dawson is an expert in the area of chemoselective ligation and was an inventor of the widely used native chemical ligation approach for the synthesis and semisynthesis of proteins. His laboratory has developed new approaches for bioconjugation, including aniline catalysis, which facilitates the synthesis of complex molecules such as vaccines and antibody-drug conjugates. The Dawson lab has used these methods to synthesize a variety of proteins to study protein folding and topology, enzymatic catalysis, homogeneous glycoproteins and mimics of the coat proteins from pathogenic viruses. His laboratory utilizes these methods for the structure based design of immunogens, the development of protein therapeutics, functionalization of nanoparticles for biological imaging and therapies for lysosomal storage diseases.
Dr. Dawson is the current Past President of the American Peptide Society (2017-2019), was co-chairman of both the 22nd American Peptide Symposium (2011) and the GRC on the Chemistry and Biology of Peptides (2016). He has published over 160 papers, and has been honored with an Alfred P. Sloan Foundation fellowship, the Vincent du Vigneaud Award, the Max Bergmann Kreis Gold Medal and the Zervas award.