Emerging Prospects for Combating Fungal Infections by Targeting Phosphatidylinositol Transfer Proteins
Danish Khan1, Aaron H Nile2, Ashutosh Tripathi3
1Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843-2128, USA.
Abstract:
The emergence of fungal "superbugs" resistant to the limited cohort of anti-fungal agents available to clinicians is eroding our ability to effectively treat infections by these virulent pathogens. As the threat of fungal infection is escalating worldwide, this dwindling response capacity is fueling concerns of impending global health emergencies. These developments underscore the urgent need for new classes of anti-fungal drugs and, therefore, the identification of new targets. Phosphoinositide signaling does not immediately appear to offer attractive targets due to its evolutionary conservation across the Eukaryota. However, recent evidence argues otherwise. Herein, we discuss the evidence identifying Sec14-like phosphatidylinositol transfer proteins (PITPs) as unexplored portals through which phosphoinositide signaling in virulent fungi can be chemically disrupted with exquisite selectivity. Recent identification of lead compounds that target fungal Sec14 proteins, derived from several distinct chemical scaffolds, reveals exciting inroads into the rational design of next generation Sec14 inhibitors. Development of appropriately refined next generation Sec14-directed inhibitors promises to expand the chemical weaponry available for deployment in the shifting field of engagement between fungal pathogens and their human hosts.
Insights
New antifungal drug targets are urgently needed due to rising fungal resistance. Sec14-like proteins offer a selective strategy to disrupt fungal phosphoinositide signaling, paving the way for novel antifungal therapies.
Area of Science:
- Mycology
- Drug Discovery
- Molecular Biology
Background:
- Increasing global fungal infections and the emergence of drug-resistant fungal strains ('superbugs') pose a significant public health threat.
- Limited therapeutic options and diminishing efficacy of existing antifungal agents necessitate the urgent development of new drug classes and targets.
- Phosphoinositide signaling pathways, while evolutionarily conserved, are being re-evaluated as potential targets for selective antifungal intervention.
Purpose of the Study:
- To explore Sec14-like phosphatidylinositol transfer proteins (PITPs) as novel targets for disrupting fungal phosphoinositide signaling.
- To highlight the potential of targeting fungal Sec14 proteins for developing next-generation antifungal drugs.
- To discuss the selective chemical disruption of phosphoinositide signaling in virulent fungi.
Main Methods:
- Review and discussion of recent evidence identifying Sec14-like PITPs as potential antifungal targets.
- Analysis of lead compounds targeting fungal Sec14 proteins from diverse chemical scaffolds.
- Exploration of rational drug design strategies for developing Sec14 inhibitors.
Main Results:
- Sec14-like PITPs represent a promising, yet underexplored, target class for selective antifungal drug development.
- Identification of lead compounds targeting fungal Sec14 proteins demonstrates the feasibility of chemical disruption.
- Diverse chemical scaffolds can be utilized for the rational design of novel Sec14 inhibitors.
Conclusions:
- Sec14-like PITPs offer a selective portal to disrupt essential phosphoinositide signaling in pathogenic fungi.
- Development of refined Sec14-directed inhibitors can significantly expand the arsenal against resistant fungal infections.
- Targeting fungal Sec14 proteins represents a viable strategy to combat the escalating threat of global fungal disease.
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