Juan Del Valle

Research Interests

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.

Selected Publications

• Rajewski, B. H.; Wright, M. M.; Gerrein, T. A. and Del Valle, J. R. "N-Aminoglycine and its Derivatives Stabilize PPII Secondary Structure" 2023 Organic Letters, 25 (23), pp.4366-4370. DOI: 10.1021/acs.orglett.3c01502.
• Elbatrawi, Y. M.; Gerrein, T.; Anwar, A.; Makwana, K. M.; Degen, D.; Ebright, R. H. and Del Valle, J. R. "Total Synthesis of Pargamicin A" 2022 Organic Letters, 24 (50), pp.9285-9289. DOI: 10.1021/acs.orglett.2c03861.
• Shao, A. D.; Xu, Q.; Kang, C. W.; Cain, C. F.; Lee, A. C.; Tang, C.; Del Valle, J. R. and Hu, C. "IRE-1-Targeting Caged Prodrug with Endoplasmic Reticulum Stress-Inducing and XBP-1S-Inhibiting Activities for Cancer Therapy" 2022 Molecular Pharmaceutics, 19 (4), pp.1059-1067. DOI: 10.1021/acs.molpharmaceut.1c00639.
• Rathman, B. M. and Del Valle, J. R. "Late-Stage Sidechain-to-Backbone Macrocyclization of N-Amino Peptides" 2022 Organic Letters, 24 (7), pp.1536-1540. DOI: 10.1021/acs.orglett.2c00204.
• Cain, C. F.; Scott, A. M.; Sarnowski, M. P. and Del Valle, J. R. "Total Synthesis and Chemical Stability of Pseudouridimycin" 2022 Chemical Communications, 58 (14), pp.2351-2354. DOI: 10.1039/d1cc07059b.
• Makwana, K. M.; Sarnowski, M. P.; Miao, J. Y.; Lin, Y. S. and Del Valle, J. R. "N-Amination Converts Amyloidogenic Tau Peptides into Soluble Antagonists of Cellular Seeding" 2021 ACS Chemical Neuroscience, 12 (20), pp.3928-3938. DOI: 10.1021/acschemneuro.1c00528.