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.

Modulators of neurodegenerative tau propagation

Several neurodegenerative diseases are characterized by misfolding and assembly of the tau protein into conformationally diverse fibrils. These fibrils can, in turn, spread from cell-to-cell leading to disease progression. We are pursuing the structure-based design and synthesis of tau mimics that can (1) nucleate elusive pathological folds, or (2) potently inhibit tau propagation across cells.

Synthesis and optimization of peptide natural products

Non-ribosomal peptides (NRPs) and ribosomally-synthesized post-translationally modified peptides (RiPPs) are promising classes of natural products with diverse biological activities. We are targeting the synthesis of several NRPs and RiPPs that harbor complex backbone modifications important for biological activity. Total synthesis provides a platform for the development of new methods and tactics, as well a launching point for conformation-activity relationship studies.

Peptide and protein mimics targeting PPIs

The development of molecules capable of disrupting protein-protein interactions (PPIs) remains a significant challenge. We are engaged in the design and synthesis of ​β-sheet mimics, stabilized polyproline II helices, and macrocyclic peptides, and in parsing the impact of chemical modifications on protein folding and stability. Our compounds are then employed to target PPIs that drive cancer, neurodegeneration, and infectious disease.

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.