Seok-Yong Lee
Duke University, NC·Biophysics
Many drugs work by attaching to proteins that sit in the membranes surrounding cells. These proteins include enzymes that build a fungus's protective wall, pumps that move small molecules in and out of cells, and sensors in nerve cells that detect cold, heat and irritants.
- Fields
Biophysics
Pharmacology
Biochemistry
- Topics
structural biology
cryo-EM
membrane proteins
- Grants
- 4 known grants, through Aug 2032
What they work on
- Determine how the echinocandin caspofungin blocks the fungal cell-wall enzyme β-1,3-D-glucan synthase (GS) and how Fks1 mutations cause resistance, using cryo-EM structures, enzyme assays and computational methods.
- Extend the structural and functional studies to other FDA-approved echinocandins to compare how each drug binds and inhibits the Fks catalytic subunit of glucan synthase.
- Uncover how ibrexafungerp (IBX), a newer antifungal class, inhibits glucan synthase and whether it stays active against echinocandin-resistant forms of Fks1.
- Explore how Fks1 builds the long glucan sugar chains of the fungal cell wall and how its regulatory partner Rho1, a switch-like protein, controls this activity, using structural biology and enzymology.
- Test in living animals whether equilibrative nucleoside transporter 1 (ENT1), the main adenosine-uptake protein, is a valid target for neuropathic pain, building on the analgesic effect of the dilazep-derived compound JH-ENT-01.
- Characterize ENT1 inhibitors in vitro and ex vivo, and develop and improve laboratory assays for screening new compounds that block this adenosine transporter.
- Determine the molecular basis by which sensory receptor ion channels in somatosensory neurons detect temperature and irritants, combining structural, functional and computational studies to build a general model of their activity.
- Study how disease mutations in sensory receptor channels lead to neuronal disorders, and develop small molecules targeting these channels as non-opioid treatments for conditions such as chronic itch and migraine.
- Define how chemical compounds open and close TRPM8, the cold- and menthol-sensing channel in eye nerves, using structural biology together with electrophysiology, which records the electrical currents that flow through ion channels.
- Design and test new TRPM8-modulating compounds through medicinal chemistry, imaging and animal model studies, as a foundation for treating dry eye disease and eye pain.
More about the research
Seeing the 3D shape of such a protein, and exactly where a drug attaches, can explain why a drug works, why it stops working, and how a better one might be designed. This research uses that approach on four problems: drug-resistant fungal infections, non-addictive pain relief, the molecular basis of touch, temperature and pain sensing, and dry eye disease. The common toolkit combines structural biology (determining protein shapes at near-atomic detail), enzyme and electrical measurements, chemical biology, computer modeling, and, in several projects, animal studies.
Why it matters
This work could help several groups of patients. Hospital patients with weakened immune systems who develop invasive Candida infections may benefit, because knowing how echinocandins and ibrexafungerp bind their target and how resistance arises could guide the design of next-generation antifungals. ENT1 inhibitors could become non-addictive alternatives to opioids for people with neuropathic pain. Drugs aimed at sensory receptors could help people with chronic pain, itch or migraine, and TRPM8-targeted compounds could treat dry eye disease and eye pain.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
David D Mckemy
University of Southern California, CA·Neuroscience
Define the cellular mechanism by which artemin and its receptor GFRα3 make TRPM8 cold-sensing neurons more sensitive after injury, producing cold allodynia.
Mahmoud Ahmed
Texas Tech University Health Sciences Center, TX·Pharmacology
Develop new small-molecule inhibitors of the EphB1/2 tyrosine kinases, nerve-signaling enzymes, that are unrelated to tetracyclines, and define the structure–activity features needed for potent inhibition.
J McIntosh
University of Utah, UT·Pharmacology
Build a library of selective probes for nicotinic acetylcholine receptor subtypes that lack them, by mining cone snail venom peptides and refining them through structure-activity relationship studies.
The school
Duke University: 61 labs on PI Pages, $1.6B a year on research, 417 research doctorates a year.
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