John Lukesh

Education

Ph.D., 2014, University of Wisconsin–Madison (Ronald T. Raines)
Postdoctorate, 2014–2017, The Scripps Research Institute (Dale L. Boger)

Research Description

The Lukesh Lab employs modern synthetic organic chemistry to create novel redox-active small molecules with unique and highly tunable biological properties. Guided by a broad interest in molecular design and its translational impact on biology and medicine, our group develops new chemical tools, therapeutic leads, and methods that illuminate and manipulate fundamental redox processes in living systems. Our current research efforts span three synergistic areas:

Chemical Biology: We develop new molecular probes, reporters, and stimuli-responsive donors to interrogate the chemical biology of reactive sulfur and selenium species (RSS/RSeS) in complex biological environments. These efforts focus on mechanistic elucidation, selective detection of fleeting entities, and the controlled delivery of species such as H₂S, COS, persulfides, polysulfides, and emerging selenium analogues. Through synthetic organic chemistry and the development of novel chemical tools, we seek to define how these species function in redox signaling, stress responses, and disease-relevant pathways.

Medicinal Chemistry: We rationally design and synthesize novel chalcogen-containing scaffolds and redox-modulating small molecules with potential therapeutic applications. By leveraging the unique reactivity profiles of chalcogen species, our group aims to develop heteroatom-rich pharmacophores, next-generation redox-activated prodrug triggers, and stimuli-responsive donors with utility in cardioprotection, oncology, and other redox-related disorders. These projects integrate SAR analysis, mechanistic understanding, and collaborative biological testing.

Synthetic Methodology Development: We pursue new synthetic strategies that exploit the reactivity of organoselenium reagents, catalysts, and intermediates. A major emphasis is placed on C–C bond-forming reactions, chalcogen-enabled heterocycle synthesis, and scalable, selective routes to privileged scaffolds. Our methodology work not only enables access to molecules of biological interest but also expands the toolbox available to the broader synthetic community.

Training Philosophy: Students in the Lukesh Lab gain broad exposure to the chemistry–biology interface, developing skills in molecular design, reaction optimization, mechanistic analysis, redox biochemistry, probe and prodrug development, and biological evaluation. Our trainees work with a diverse set of chemical and biological approaches that prepare them for impactful careers in academia, biotechnology, pharmaceuticals, and related interdisciplinary fields.

Selected Publications

“Stimulus-Responsive Perselenide, Thioselenide, and Selenosulfide Donors for Reactive Selenium Species Chemical Biology,” Tripathi, R.; Hankins, R. A.; Yi, J.; Liu, L.; Presti, R. S.; Cohen, M. H.; Sawase, L. R.; Luna, T. D.; Ding, W.; Lukesh, J. C. J. Am. Chem. Soc. 2026, 148, 10599–10607. https://doi.org/10.1021/jacs.5c19556

“Esterase-Activated Hydrogen Sulfide Donors with Self-Reporting Fluorescence Properties and Highly Tunable Rates of Delivery,” Zhu, C.; Chen, C.; Weaver, D. E.; Lukesh, J. C. ACS Chem. Biol. 2024, 19, 1910–1917. https://doi.org/10.1021/acschembio.4c00396

“An ROS-Responsive Donor That Self-Reports Its H₂S Delivery by Forming a Benzoxazole-Based Fluorophore,” Hu, Q.; Zhu, C.; Hankins, R. A.; Murmello, A. R.; Marrs, G.; Lukesh, J. C., III. J. Am. Chem. Soc. 2023, 145, 25486–25494. https://doi.org/10.1021/jacs.3c10446

“Enol-Mediated Delivery of Hydrogen Selenide from 𝛾-Keto Selenides: Mechanistic Insight and Evaluation,” Hankins, R. A.; Carter, M. E.; Zhu, C.; Chen, C.; Lukesh, J. C., III. Chem. Sci. 2022, 13, 13094–13099. https://doi.org/10.1039/D2SC03533B

“Intramolecular Thiol- and Selenol-Assisted Delivery of Hydrogen Sulfide,” Hu, Q.; Suarez, S. I.; Hankins, R. A.; Lukesh, J. C., III. Angew. Chem. Int. Ed. 2022, 61, e202210754. https://doi.org/10.1002/anie.202210754

“Arylselenyl Radical-Mediated Cyclization of N-(2-alkynyl)anilines: Access to 3-Selenylquinolines,” Zhu, C.; Nurko, M.; Day, C. S.; Lukesh, J. C., III. J. Org. Chem. 2022, 87, 8390–8395. https://doi.org/10.1021/acs.joc.2c00282

“Mitigating Doxorubicin-Induced Cardiotoxicity with an H₂O₂-Activated, H₂S-Donating Hybrid Prodrug,” Hu, Q.; Yammani, R. D.; Brown-Harding, H.; Soto-Pantoja, D. L.; Poole, L. B.; Lukesh, J. C., III. Redox Biol. 2022, 53, 102338–102346. https://doi.org/10.1016/j.redox.2022.102338

“An Innovative Hydrogen Peroxide-Sensing Scaffold and Insight Towards its Potential as an ROS-Activated Persulfide Donor,” Hankins, R. A.; Suarez, S. I.; Kalk, M. A.; Green, N. M.; Harty, M. N.; Lukesh, J. C., III. Angew. Chem. Int. Ed. 2020, 59, 22238-22245. https://doi.org/10.1002/anie.202010530

INVITED COVER ARTICLE: “Selenosulfides Tethered to gem-Dimethyl Esters: A Robust and Highly Versatile Framework for H₂S Probe Development,” Suarez, I. S.; Ambrose, R.; Kalk, M. A.; Lukesh, J. C., III. Chem. Eur. J. 2019, 25, 15736–15740. https://doi.org/10.1002/chem.201904133 

Awards and Accomplishments

• Wake Forest University Award for Excellence in Research, 2025
• NIH NIGMS Maximizing Investigators’ Research Award (MIRA), 2024–2029
• F. M. Kirby Family Faculty Fellowship, 2022–2025
• NSF CAREER Award, 2022–2027