- William K. Warren Family Associate Professor, University of Notre Dame
- Associate Professor, University of South Florida
- Assistant Professor, University of South Florida and Moffitt Cancer Center
- Assistant Professor, New Mexico State University
- Postdoctoral Scholar, University of Montreal
- Ph.D. in Chemistry, University of California San Diego
- B.A. in Chemistry, Carleton College
- Undergraduate Teaching Award, University of South Florida
- CIBA Young Scientist Award, ACS Younger Chemists Committee
- Milestone Award, Miles for Moffitt Foundation
The Del Valle lab is broadly interested in bringing the power of organic chemistry to bear on current challenges in drug discovery and biomolecular recognition. Our research program lies at the interface of organic synthesis and chemical biology, with an emphasis on the structure-based design of biologically active peptidomimetics and small molecules. We view non-canonical peptides and stabilized protein folds as the ‘next wave’ in drug discovery, and we are working to realize their promise as potential therapeutics.
Constrained peptides targeting protein-protein interactions
Despite the importance of well-defined protein-protein interactions (PPIs) in promoting various diseases, the development of molecules capable of modulating these interactions remains a significant challenge. This situation stems from a chemical biology paradox in which the need to bind large protein surfaces with precise topology is beset by the flexibility and cell-impermeability of high molecular weight inhibitors. Our lab is targeting a number of PPIs using designed protein mimics. Efforts in this area include disruption of neurodegenerative protein aggregation as well as PPIs that drive cancer and autoimmune disorders.
Synthesis and SAR of non-ribosomal peptide natural products
Nature remains a prolific source of drug candidates, with almost half of all FDA-approved therapeutics classified as natural product derived or inspired. Non-ribosomal peptides (NRPs) represent a particularly promising class of natural products with diverse biological activities. NRPs are predisposed to interact with protein receptors and often feature drug-like properties not typically seen in canonical polypeptides. We are pursuing the synthesis of NRPs in which unusual amino acids or unique backbone modifications are important for biological activity. We also leverage synthetic access to these residues in order to study their effects on native peptide/protein conformation and their utility in other drug design applications.
Modulators of ER stress response
Endoplasmic reticulum (ER) stress resulting from gene amplification and aberrant protein expression is an established hallmark of cancer. As a result, many tumors hijack ER stress response mechanisms in order to evade cell death. As part of a highly collaborative effort with immunologists, cell biologists, and clinicians, our lab has developed a series of potent inhibitors of the IRE1/XBP1 signaling arm of the ER stress response. These compounds have helped to establish the clinical relevance of targeting IRE1 in a variety of disease models including chronic lymphocytic leukemia, c-Myc-driven cancers, and graft-versus-host disease. Current efforts are aimed at chemical optimization, advanced pre-clinical development, and elucidating the role of ER stress response in other diseases using new chemical probes.
- Rathman, B. M., Allen, J. L., Shaw, L. N., Del Valle, J. R. "Synthesis and biological evaluation of backbone-aminated analogues of gramicidin S" 2020 Bioorganic and Medicinal Chemistry Letters, 30 (15), 127283. DOI:10.1016/j.bmcl.2020.127283.
- Sarnowski, M. P., Del Valle, J. R. "N-Hydroxy peptides: solid-phase synthesis and ß-sheet propensity" 2020 Organic and Biomolecular Chemistry, 18 (19), pp. 3690-3696. DOI:10.1039/d0ob00664e.
- Elbatrawi, Y. M., Pedretty, K. P., Giddings, N., Woodcock, H. L., Del Valle, J. R. "δ-Azaproline and Its Oxidized Variants" 2020 Journal of Organic Chemistry, 85(6), pp.4207-4219. DOI:10.1021/acs.joc.9b03384.
- Howard, E. H., Cain, C. F., Kang, C., Del Valle, J. R. "Synthesis of Enantiopure ϵ-Oxapipecolic Acid" 2020 Journal of Organic Chemistry, 85 (3), pp. 1680-1686. DOI:10.1021/acs.joc.9b02382.
- Shao, A., Kang, C. W., Tang, C. -. A., Cain, C. F., Xu, Q., Phoumyvong, C. M., Del Valle, J. R., Hu, C. -. A. "Structural Tailoring of a Novel Fluorescent IRE-1 RNase Inhibitor to Precisely Control Its Activity" 2019 Journal of Medicinal Chemistry, 62 (11), pp. 5404-5413. DOI:10.1021/acs.jmedchem.9b00269.
- Elbatrawi, Y. M., Kang, C. W., Del Valle, J. R. "Total Synthesis of L-156,373 and an oxoPiz Analogue via a Submonomer Approach" 2018 Organic Letters, 20 (9), pp. 2707-2710. DOI:10.1021/acs.orglett.8b00912.