From Naturally-Sourced Protease Inhibitors to New Treatments for Fungal Infections

Abstract

Proteases are involved in a broad range of physiological processes, including host invasion by fungal pathogens, and enzymatic inhibition is a key molecular mechanism controlling proteolytic activity. Importantly, inhibitors from natural or synthetic sources have demonstrated applications in biochemistry, biotechnology, and biomedicine. However, the need to discover new reservoirs of these inhibitory molecules with improved efficacy and target range has been underscored by recent protease characterization related to infection and antimicrobial resistance. In this regard, naturally-sourced inhibitors show promise for application in diverse biological systems due to high stability at physiological conditions and low cytotoxicity. Moreover, natural sources (e.g., plants, invertebrates, and microbes) provide a large reservoir of undiscovered and/or uncharacterized bioactive molecules involved in host defense against predators and pathogens. In this Review, we highlight discoveries of protease inhibitors from environmental sources, propose new opportunities for assessment of antifungal activity, and discuss novel applications to combat biomedically-relevant fungal diseases with in vivo and clinical purpose.

Differentiated extracts from freshwater and terrestrial mollusks inhibit virulence factor production in Cryptococcus neoformans

“…During the last 20 years, multiple compounds, including antimicrobial peptides and peptidase inhibitors, have been identi ed with activity against human fungal pathogens 9 . However, most investigations focused on killing the pathogen (i.e., fungicidal effect) rather than inhibiting virulence factors (i.e., fungistatic effect), and only a few have been reported from invertebrates 42 . These fungicidal compounds exert high selective pressure and promote the development of resistance mechanisms, affecting long-term clinical uses.…”

Expanding the therapeutic options for Candida infections using novel inhibitors of secreted aspartyl proteases

“…Pepstatin A, a peptide analog, is a potent inhibitor of aspartyl proteases. However, it is not used in clinical practice due to its high hepatotoxicity and low bioavailability (Bondaryk et al, 2017; Gutierrez‐Gongora & Geddes‐Mcalister, 2021; Rüchel et al, 1990). Peptidomimetic inhibitors for CAL SAP2 have been previously explored by Calugi et al.…”

Fungal Proteases as Emerging Biocatalysts to Meet the Current Challenges and Recent Developments in Biomedical Therapies: An Updated Review

“…There are several protease inhibitors that showed broad spectrum inhibitory specificity and antifungal activity by tight binding [225] (see Table 5). These inhibitors are survivin (cysteine inhibitor) [226,227], diosgenin (metalloprotease inhibitor) [228,229], serpin (serine inhibitor) [230], saccharopepsin (aspartic acid inhibitor) (IA3) [231], streptomyces (metallopeptidase inhibitor; SMI) [232], RFLP-1 (Rhamnus frangula inhibitor) proteases [233]. These protease inhibitors have gained special importance in biomedicine.…”