About TSRI
Research & Faculty
News & Publications
Scientific Calendars
Scripps Florida
PhD Program
Campus Services
Work at TSRI
TSRI in the Community
Giving to TSRI
Site Map & Search

The Skaggs Institute
for Chemical Biology

Scientific Report 2007

Design of Targeted Anticancer Agents and Synthetic Aminoacyl Transfer Catalysts

M.R. Ghadiri, J.M. Beierle, A. Chavochi, Z.Z. Huang, L. Leman, A. Montero, C.A. Olsen

We are interested in devising molecular and supramolecular processes to control the structure and function of de novo designed peptides. These efforts include the design of potent anticancer agents based on conformationally homogenous low molecular weight cyclic peptides and fabrication of self-assembling helical peptides that mimic the intermodular aminoacyl transferase activity of nonribosomal peptide synthetases.

Histone-Deacetylase Inhibitors Based on Novel 3-Dimensional Rigid Scaffolds

Because of their key roles in the transcriptional regulation of a number of genes involved in cell proliferation, cell-cycle progression, differentiation, and apoptosis, histone-deacetylase (HDAC) inhibitors have emerged as important new and validated targets in the design of anticancer drugs. Our efforts to design and discover novel HDAC inhibitors are based on the rational design of small-molecule peptide scaffolds with predictable and conformationally homogenous 3-dimensional structures. In contrast to the considerable advances made in drug design based on 2-dimensional rigid scaffolds, little progress has been made in devising effective 3-dimensional scaffolds that can act on designated biological targets (receptors) by mimicking the 3-dimensional structural features of the native biological ligands–most often peptides and proteins.

We recently developed 12-, 13-, and 14-membered peptidomimetic scaffolds that can mimic precisely side-chain juxtaposition and functional-group presentations of the 4 residues that make up β-turn structures. Structural analyses based on x-ray crystallography, 2-dimensional 1H nuclear magnetic resonance spectroscopy, and distance-geometry calculations confirmed that these scaffolds adopt rigid and conformationally homogenous 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 and to establish the pharmacophoric requirements (Fig. 1). We then used these scaffolds to design a series of potent HDAC inhibitors (IC50 <20 nM) that target several class I and class II HDACs. These compounds also have anticancer activities against a number of human tumor cell lines.

Fig. 1. Chemical structures of the natural HDAC inhibitor apicidin (top) and the synthetic heterocyclic analog (middle) and the solution nuclear magnetic resonance structure indicating the β-turn–like rigid backbone conformation and side-chain display (bottom).

We hope that our basic research in establishing novel structure-based drug design concepts will result in clinically useful human anticancer chemotherapeutic agents. Moreover, because the constrained cyclic 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 will have applications in other structure-based approaches to rational drug design.

Synthetic Aminoacyl Transfer Catalysts

Ribosomes, nonribosomal peptide synthetases, and polyketide synthetases are biological machines that catalyze instructed chemical synthesis, a phenomenon not yet matched by any synthetic system. Although chemists have amassed a remarkable record of achievements in devising peptide catalysts that carry out single-step chemical reactions, the phenomenon of autonomous instructed synthesis has remained beyond reach. We have focused on the design of catalysts that can mimic the sequential aminoacyl transferase activity of nonribosomal peptide synthetases.

We have designed several modular supramolecular peptide constructs that efficiently promote site-specific aminoacyl transfer between noncovalently associated α-helical subunits in neutral aqueous solutions. These constructs have some of the basic hallmarks of natural enzymes, including precise positioning of active-site residues, covalent catalysis, general acid-base catalysis, pKa modulation of active-site residues, and multiple product turnovers (Fig. 2).

Fig. 2. Schematic representations of aminoacyl loading and intermodular aminoacyl transfer in nonribosomal peptide synthetases (A) and designed coiled coil catalysts (B). C, Active-site residues of an aminoacyl transfer catalyst modeled onto the crystal structure of a coiled coil homotetramer. Sequences of peptides used in the current studies are shown on the right.

More recently, we have engineered peptides that can mimic more complex, multistep biosynthetic processes. One example is the formation of diketopiperazine, which minimally requires simultaneous binding and activation of 2 aminoacyl substrates, aminoacyl transfer to generate a linear dipeptide intermediate, and cyclization of the dipeptide to yield the product diketopiperazine. We have designed supramolecular peptide assemblies that catalyze diketopiperazine and dipeptide synthesis for a variety of aminoacyl substrates. The peptides covalently capture 2 aminoacyl substrates from solution, hold them in proximity to bring about an effective intramolecular aminoacyl transfer, and then release product in the form of diketopiperazine (Fig. 2). We hope that these studies will help establish the basic blueprint for the future de novo design of programmable peptide synthetases.


Leman, L.J., Weinberger, D.A., Huang, Z.-Z., Wilcoxen, K.M., Ghadiri, M.R. Functional and mechanistic analyses of biomimetic aminoacyl transfer reactions in de novo designed coiled coil peptides via rational active site engineering. J. Am. Chem. Soc. 129:2959, 2007.

Wilcoxen, K.M., Leman, L.J., Weinberger, D.A., Huang, Z.-Z., Ghadiri, M.R. Biomimetic catalysis of intermodular aminoacyl transfer. J. Am. Chem. Soc. 129:748, 2007.


M. Reza Ghadiri, Ph.D.

Ghadiri Web Site