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Updated: Jul 20, 2025
Quantifying the Antifungal Activity of Peptides Against Candida albicans
Published on: January 13, 2023
Disrupting the Dok3-Card9 Interaction with Synthetic Peptides Enhances Antifungal Effector Functions of Human
Jia Tong Loh1, Joey Kay Hui Teo1, Srinivasaraghavan Kannan2
1Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, Singapore S138648, Singapore.
Abstract:
Invasive fungal disease is an emerging and serious public health threat globally. The expanding population of susceptible individuals, together with the rapid emergence of multidrug-resistant fungi pathogens, call for the development of novel therapeutic strategies beyond the limited repertoire of licensed antifungal drugs. Card9 is a critical signaling molecule involved in antifungal defense; we have previously identified Dok3 to be a key negative regulator of Card9 activity in neutrophils. In this study, we identified two synthetic peptides derived from the coiled-coil domain of Card9, which can specifically block Dok3-Card9 binding. We showed that these peptides are cell-permeable, non-toxic, and can enhance antifungal cytokine production and the phagocytosis of human neutrophils upon fungal infection. Collectively, these data provide a proof of concept that disrupting the Dok3-Card9 interaction can boost the antifungal effector functions of neutrophils; they further suggest the potential utility of these peptide inhibitors as an immune-based therapeutic to fight fungal infection.
Insights
Novel peptides targeting the Dok3-Card9 interaction enhance neutrophil antifungal activity. This immune-based strategy offers a promising new approach to combat invasive fungal infections and drug-resistant fungi.
Area of Science:
- Immunology
- Microbiology
- Drug Discovery
Background:
- Invasive fungal diseases pose a growing global health risk, exacerbated by increased susceptible populations and multidrug-resistant fungal pathogens.
- Existing antifungal drugs are limited, necessitating novel therapeutic strategies.
- Card9 is a key signaling molecule in antifungal defense, with Dok3 identified as a negative regulator of Card9 in neutrophils.
Purpose of the Study:
- To identify therapeutic strategies that enhance the innate immune response against fungal infections.
- To investigate the potential of disrupting the Dok3-Card9 interaction to boost neutrophil antifungal functions.
Main Methods:
- Identification of synthetic peptides targeting the coiled-coil domain of Card9 to block Dok3-Card9 binding.
- Assessment of peptide cell permeability and toxicity in human neutrophils.
- Evaluation of peptide effects on antifungal cytokine production and phagocytosis by neutrophils during fungal infection.
Main Results:
- Two synthetic peptides were identified that specifically inhibit Dok3-Card9 binding.
- These peptides were found to be cell-permeable and non-toxic to human neutrophils.
- Treatment with these peptides enhanced antifungal cytokine production and neutrophil phagocytosis of fungi.
Conclusions:
- Disrupting the Dok3-Card9 interaction is a viable strategy to enhance neutrophil antifungal effector functions.
- These peptide inhibitors represent a potential immune-based therapeutic approach for treating fungal infections.
- Further development of these peptides could lead to new treatments against invasive and drug-resistant fungal pathogens.
