Aspartic Protease Inhibitors as Potential Anti-Candida albicans Drugs: Impacts on Fungal Biology, Virulence and Pathogenesis

Abstract

Mycoses are still one of the most problematic illnesses worldwide, especially affecting immunocompromised individuals. The development of novel antifungal drugs is becoming more demanding every day, since existing drugs either have too many side effects or they tend to lose effectiveness due to the resistant fungal strains. In this scenario, Candida albicans is still the main fungal pathogen isolated in hospitals. Pathogenicity results essentially from modifications of the host defense mechanisms that secondarily initiate transformations in the fungal behavior. The pathogenesis of C. albicans is multifactorial and different virulence attributes are important during the various stages of infection. Some virulence factors, like the secreted aspartic proteases (Saps), play a role in several infection stages and the inhibition of one of the many stages may contribute to the containment of the pathogen and thus should help in the treatment of disease. Therefore, Saps are potential targets for the development of novel anti-C. albicans drugs. Herein, we review the beneficial properties of pepstatin A and aspartic-type protease inhibitors used in the anti-human immunodeficiency virus chemotherapy on C. albicans, with particular emphasis in the effects on Sap activity, proliferation, morphogenesis (yeasts into mycelia transformation), ultrastructural architecture, adhesion to mammalian cells and abiotic materials, modulation of unrelated virulence factors (e.g., surface glycoconjugates, lipases and sterol), experimental candidiasis infection as well as synergistic properties when conjugated with classical antifungals. Collectively, these positive findings have stimulated the search for novel natural and/or synthetic pharmacological compounds with anti-aspartic protease properties against the human opportunistic fungus C. albicans.

Fungal Enolase, β-Tubulin, and Chitin Are Detected in Brain Tissue from Alzheimer’s Disease Patients

“…Even for fungal species that do not synthesize mycotoxins, the continuous secretion of lytic enzymes could contribute to their virulence and pathogenesis for cells. Indeed, a number of lytic enzymes that digest proteins and lipids are secreted by fungi (Braga-Silva and Santos, 2011). This would be particularly detrimental for neurons containing intracellular fungi, as described here and in other studies (Pisa et al, 2015a,b).…”

HIV Aspartic Peptidase Inhibitors Modulate Surface Molecules and Enzyme Activities Involved with Physiopathological Events in Fonsecaea pedrosoi

“…Then, fungal cells were analyzed in a flow cytometer (FACSCalibur; BD Bioscience) equipped with a 15-mW argon laser emitting at 488 nm. Each experimental population was mapped ( n = 10,000 events) using a two parameter histogram of forward-angle light scatter (FSC) versus side scatter (SSC), respectively, to evaluate cellular size and granularity (Braga-Silva and Santos, 2011). …”

Candida and candidiasis in HIV-infected patients

“…This finding, in conjunction with some clinical impressions [94,95], has led ourselves and others to postulate that the early, dramatic reduction of OPC in patients under ART is also due to a direct anticandidal activity of HIV proteinase inhibitors present in ART, adding, and perhaps also favoring, the known immune reconstitution of CD4 cells [94][95][96][97][98]. These observations have been expanded to other fungi [99,100] and malaria parasites [101] and have generated interest in novel class of anticandidal drugs having Sap as a target [102].…”