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Decoding the structure, function and pharmacology of TOK Channels from human-pathogenic fungi

Award Number: R01AI198222
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/09/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Decoding the structure, function and pharmacology of TOK Channels from human-pathogenic fungi - Project Summary/Abstract Fungal pathogens Candida albicans and Aspergillus fumigatus kill millions annually worldwide and are especially dangerous for immunocompromised and aging individuals. The estimated annual economic burden of fungal diseases in the U.S. alone was $11.5 billion in 2019. Despite advances in antifungal therapies, there is a critical need for new molecular targets that bypass evolving resistance mechanisms. This project focuses on TOK channels, a fungal-specific family of potassium channels that control key physiological processes and have not been explored as antifungal targets. Recent breakthroughs in cryo-electron microscopy and electrophysiological assays offer new opportunities to define TOK channel architecture, gating, and ligand engagement at near- atomic resolution. The research in this project will determine high-resolution structures of C. albicans TOK (CaTOK) and A. fumigatus TOK1 (AfTOK1) in various functional states and identify small-molecule modulators that selectively alter channel activity, their mechanism of action at high-resolution, and their effect on fungal growth. Structural insights and comparative analyses will clarify whether these channels share core gating mechanisms while exhibiting distinct binding pockets suited for targeted inhibition. By mapping critical residues through site-directed mutagenesis and linking structural conformations to changes in rectification and ion selectivity, the work will reveal how TOK function underpins fungal fitness under stress, building an unprecedented picture of a highly unexplored potassium channel family and its gating and modulation. The expected translational outcome is a comprehensive framework for developing specialized inhibitors that beneficially modulate either CaTOK or AfTOK1, paving the way for antifungal agents that minimize off-target complications in mammalian cells. These findings will address pressing clinical demands for novel strategies to curb fungal drug resistance.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $740,595 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	1	7/9/2026	NEW	$740,595
														Subtotal = $740,595

Grand Total All Awards = $740,595

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Decoding the structure, function and pharmacology of TOK Channels from human-pathogenic fungi

Award Number: R01AI198222

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/09/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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