Chemoselective strategies for the synthesis of complex assemblies of peptide
Phil Dawson
Scientist, Scripps Institute
Chemical ligation approaches have become essential tools for the?engineering of complex molecules including proteins, nucleic acids and? nanoparticles. What makes these reactions so useful is their compatibility? with the biological "solvent" water, and a high level of chemoselectivity? that enables their application in complex molecular environments. We have? worked to develop several ligation chemistries that are highly? chemoselective and have sufficient ligation rates to be useful at low? concentrations. In one case, the use of hydrolysis resistant thioester? peptides that undergo inter- and intramolecular acyl transfer enables the total synthesis of proteins. The optimization of the ligation methodology, improved routes to the required peptide intermediates, and application of these methods to complex targets will be presented. Another challenge is the covalent assembly of macromolecules and nanoparticles. In these systems, a "native" linkage is irrelevant and the main criteria for a successful ligation methodology are fast reaction rates and high?chemoselectivity. We have found that aniline catalyzed hydrazone and oxime? reactions enable the controlled assembly and disassembly of macromolecular?complexes in aqueous solution at micromolar concentrations. The scope of?these reactions and new approaches for their catalysis will be discussed.
Philip Dawson is an Associate Professor of Chemistry at The Scripps Research Institute (TSRI) in La Jolla, CA. His research focuses on the development of new synthetic tools for protein chemistry and their application in the areas of nanotechnology, HIV vaccine development, targeted imaging and protein boiphysics.