Structural analyses based on x-ray crystallography, 2-dimensional 1H nuclear magnetic resonance spectroscopy, and distance-geometry calculations confirmed that the heterocyclic peptide scaffolds adopt rigid and conformationally homogeneous β-turn structures in solution and in the solid state. We have used this approach to probe the bioactive conformations of natural cyclic tetrapeptide HDAC inhibitors.
Because of their key roles in the transcriptional regulation of a number of genes involved in cell proliferation, cell-cycle progression, differentiation, and apoptosis, HDACs are important new targets in the design of novel anticancer agents. Our studies indicate that appropriately designed triazole modified cyclic peptides can have potent HDAC inhibitory activities, rivaling those of many previously known natural and synthetic HDAC inhibitors. Moreover, because our constrained heterocyclic scaffolds can be used to display a variety of amino acid side chains and backbone geometries in specific and predictable 3-dimensional arrangements, we think that our basic design concepts can have applications in other structure-based approaches for rational design of drugs.
Synthetic Peptide Catalysts
Rational design of biomolecular catalysts is a fundamentally valuable enterprise for assessing and advancing our basic understanding of factors that contribute to the functioning of natural enzymes. We are interested in the aminoacyl transfer class of reactions because of their prominent roles in a number of chemical and biological processes. Specifically, we are interested in mimicking the sequential aminoacyl transferase activity of nonribosomal peptide synthetases, enzymes responsible for the production of many natural products used as therapeutic agents.
Our designed catalyst is a modular peptide
construct that can promote stoichiometric and site-specific aminoacyl transfers between noncovalently
subunits with catalytic efficiencies >106 in neutral aqueous solutions. We have
used x-ray crystallography and nuclear magnetic resonance spectroscopy to analyze the structural
and functional features of the aminoacyl transferase designs (Fig. 2). We hope that these studies
will establish the basic blueprint for the future de novo design of programmable peptide synthetases.