Neal J. Zondlo

Biography

​(b. 1970) B.A., 1992, Rice University; Ph.D., 1999, Yale University; NIH Postdoctoral Fellow, 1999 – 2001, Harvard University

Current Research

Biological targets represent a considerable test of our knowledge of the fundamental principles of molecular recognition. Effective modulation of biological events requires the generation of molecules with both high affinity and high specificity for the desired target. Our interests center on the general area of functional molecular recognition: the generation of novel molecular structures and architectures which interact specifically with target molecules. Our research focuses on the synthesis and development of small molecules and minimalist polymers with biological activity, the elucidation of fundamental principles of and discovery of effectors of biological interactions, the development of novel, functional proteins, and the development of novel and useful methods of enantioselective catalysis.

Small Molecule Proteomimetics:

Work in genomics and proteomics is revealing vast numbers of interaction loci within the cellular milieu, and thus vast numbers of potential targets for agonists and antagonists of protein-protein, protein-DNA and protein-RNA interactions. Our focus is the use of molecular design and organic synthesis to develop small molecules which mimic larger biological structures. Our work involves the development of appropriate, readily accessible organic scaffolds, in solution and on solid phase, using modern methods of organic synthesis. To evaluate our scaffolds they are subjected to high-throughput testing for biological activity. Modularity in synthesis allows the combination of multiple structural elements to allow recognition of larger protein surfaces and the synthesis of multifunctional "proteins." The postgenomic era requires novel tools to elucidate en masse the identity, classes and modes of proteinprotein interactions in disparate cell types, developmental stages, and intracellular environments, in addition to changes due to age and disease states. The ability to generate small molecule mimics of protein recognition elements permits their use as chemical probes of protein-protein interactions.

Enantioselective Catalysis:

Effective, selective catalysis requires molecular functionality sufficient for catalytic activity, (regio- and stereo-) discrimination in substrate recognition enforced by reproducible transition state geometry, rapid association of substrate and dissociation of product to ensure turnover, and a partially open geometry to allow significant substrate scope. The incorporation of catalytic functionality within a designed structure is an important goal, and provides a critical test of our knowledge of the fundamental principles of molecular folding and catalysis. Due to their inherent chirality and structure, peptides and designed proteins are ideally situated to function as highly effective catalysts, despite limited success to date. Our approach is to modify known metal-binding peptides and to design novel metal-binding peptides cabable of functioning as effective catalysts, based on our knowledge of the structure and electronics of known catalysts. A second element to catalyst discovery is the ability to rapidly screen catalyst candidates. To address the scope of combinatorial space, both in terms of catalyst structure and substrate generality, we are developing new methods for high-throughput screening for catalysis. These methods are designed to be applicable not only to the discovery of protein- and peptide-based catalysts, but also toward the discovery of metal-complexbased catalysts and organocatalysts.

Protein Misfolding and Disease:

Numerous disease states, including Alzheimer's disease, Parkinson's disease and spongiform encephalopathies (i.e. mad cow disease and its human variants), are characterized by protein misfolding and precipitation which is central to the observed pathology. We are interested in the molecular mechanisms leading from the soluble, monomeric to the insoluble, polymeric protein forms. To address these issues we are examining the determinants of thermodynamic stability of postulated intermediate structures, including systematic and high-throughput analyses and synthesis of novel amino acids to test mechanistic hypotheses.

Representative Publications

S. Balakrishnan and N. J. Zondlo "Design of a Protein Kinase-Inducible Domain," J. Am. Chem. Soc.128

A. A. Bielska and N. J. Zondlo "Hyperphosphorylation of tau Induces Local Polyproline II Helix," Biochemistry45

K. M. Thomas, D. Naduthambi and N. J. Zondlo "Electronic Control of Amide cis-trans Isomerism via the Aromatic-Prolyl Interaction," J. Am. Chem. Soc.128

K. M. Thomas, D. Naduthambi, G. Tririya and N. J. Zondlo "Proline Editing: A Divergent Strategy for the Synthesis of Conformationally Peptides," Org. Lett. 7