# Dual-Activity Inhibitors Targeting Aspergillus fumigatus PanK for Antifungal Therapy

> **NIH AI R21** · YALE UNIVERSITY · 2026 · $283,926

## Abstract

Research Summary
Invasive aspergillosis (IA), primarily caused by Aspergillus fumigatus, is a life-threatening infection that
predominantly affects immunocompromised individuals. Despite advancements in antifungal treatments, IA is
associated with high mortality rates; for instance, among solid organ transplant recipients, mortality rates range
from 65% to 92%, with IA contributing to approximately 9.3%–16.9% of all deaths within the first-year post-
transplantation. A. fumigatus is also an important cause of fungal keratitis (FK), a site-threatening corneal
infection that occurs in otherwise healthy patients that experience corneal trauma. As with IA, visual outcomes
associated with FK are also poor, with 70% of all patients experiencing reduced or complete loss of vision in the
affected eye. These statistics underscore the urgent need for novel therapeutic strategies for both pulmonary
and corneal A. fumigatus infection. Pantothenate kinases are essential enzymes involved in the biosynthesis of
coenzyme A (CoA and Acetyl-CoA (AcCoA) (The PCA pathway). Our studies have demonstrated that inhibition
of PanK activity and the PCA pathway not only impedes fungal growth but also disrupts vacuolar function,
compromising the pathogen's ability to detoxify antifungal agents. This dual mechanism suggests that PanK
inhibitors can serve both as standalone drugs and as potentiators of existing antifungal drugs. We previously
screened a library of 256,000 compounds against A. fumigatus AfPanK and identified pyrimidone triazoles
(PTZs) as potent and selective inhibitors of this essential enzyme. Using structure-activity relationship (SAR)
studies we designed and synthesized a focused library of 113 PTZ analogs. The goal of this R21/R33 proposal
is to evaluate the biochemical activity, pharmacological properties and in vitro and in vivo efficacy of these
compounds and identify potent dual-activity PTZ molecules to develop as novel antifungal agents against A.
fumigatus infection. 

## Key facts

- **NIH application ID:** 11266453
- **Project number:** 1R21AI195355-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** CHOUKRI  BEN MAMOUN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $283,926
- **Award type:** 1
- **Project period:** 2026-05-06T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11266453

## Citation

> US National Institutes of Health, RePORTER application 11266453, Dual-Activity Inhibitors Targeting Aspergillus fumigatus PanK for Antifungal Therapy (1R21AI195355-01). Retrieved via AI Analytics 2026-07-12 from https://api.ai-analytics.org/grant/nih/11266453. Licensed CC0.

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