Natural Product-Inspired Peptide Cyclization Strategies and Their Therapeutic Applications

Peptide cyclization methods are useful in the development of therapeutic peptide leads with improved metabolic stability properties. To develop residue-selective peptide cyclization strategies, we draw inspiration from cyclic and lassoed peptide natural product scaffolds that exhibit diverse biological activities. For example, the reactive phenolic linkages found in both the arylomycin and vancomycin families of antibacterial natural products motivated us to develop simple-to-perform oxidative methods that generate electrophilic 1,2,4-triazoline-3,5-dione moieties on native peptides to ultimately achieve residue-selective cyclizations (Keyes et al. J. Am. Chem. Soc. 2023, 145, 10071). In awe of lasso peptides, non-covalently interlocked and proteolytically-stable bioactive natural products, we are working in collaboration with the Swanson laboratory to develop and understand strategies for reversible isopeptide bond formation that could enable the sequence-independent chemical synthesis of lasso peptides. Detailed accounts of these developments and their applications will be presented.

Bio: Andrew G. Roberts was born and raised in Long Beach, California. He earned his B.S. Chemistry degree in 2008 from UC San Diego where he first learned organic synthesis with Dr. Haim Weizman in the Tor laboratory. Andrew then conducted his Ph.D. thesis research concerning the total chemical synthesis of dimeric pyrrole-imidazole alkaloid natural products with Prof. Patrick G. Harran at UC Los Angeles (2008–2013). These bioactive and synthetically challenging molecules enabled the development of chemical methods for guanidine synthesis and manipulation. He went on to conduct postdoctoral research with Prof. Samuel J. Danishefsky at Memorial Sloan Kettering Cancer Center as an NIH postdoctoral fellow (2013–2017). This experience provided two opportunities to address questions at the interface of synthetic protein chemistry and cancer biology. Andrew collaborated with two teams to complete the chemical protein synthesis and evaluation of granulocyte colony-stimulating factor (G-CSF) and oncogenic KRas(G12V) proteins, with respective support from Drs. Moore (MSKCC) and Verdine (Harvard). Both synthetic protein targets enabled the development of novel strategies for peptide ligation and demonstrated efficient chemical protein synthesis endeavors. Research in the Roberts laboratory (University of Utah, Department of Chemistry) is focused on the discovery of novel reactions to enable the synthesis of bioactive natural products, natural product mimics, and the design of structure-stabilized peptide therapeutics.