Exploring the mechanisms behind the anti-cryptococcal potential of an extracellular vesicle tripeptide targeting dipeptidyl peptidase 4 – Institute of Fiocruz

Lead applicant

Professor Marcio Rodrigues – Institute of Fiocruz

Co-applicants

Taicia P. Fill – Chemistry Institute of University of Campinas

Geographical focus – Brazil and other LMICs

Research Theme – Microbial Pathogenesis

Lay summary

The therapeutic alternatives currently available for combating cryptococcosis have their effectiveness compromised by high costs, toxicity, and antifungal resistance. Our most recent results indicate that a peptide identified in extracellular vesicles of Cryptococcus deuterogattii controls the cryptococcal colonization of the lungs and brains in lethally infected mice. This peptide, formed by the isoleucine-proline-isoleucine (IPI) sequence, inhibits the enzyme dipeptidyl peptidase IV (DPP4). In mammals, this enzyme controls the concentrations of glucagon-like peptide I (GLP-1), a metabolic regulator that also controls intracranial pressure (ICP). Elevated ICP is a major issue during cryptococcosis. In fungi, DPP4 is not essential for growth but participates in pathogenicity.In this proposal, we will determine the potential of IPI as an alternative to combat cryptococcosis, alone or in combination with standard antifungals. We will determine its mechanism of action by assessing its role on fungal and host DPP4, including its ability to regulate ICP through the modulation of GLP-1 concentration. In summary, we are presenting a novel antifungal candidate with a defined cellular target to fight cryptococcal diseases. This candidate is not prone to be affected by antifungal resistance, as it targets a non-essential fungal enzyme in association with a physiological event in the host. Therefore, if successful, this proposal can characterize IPI as an accessory tool in the fight against cryptococcosis.