Protease expression by microorganisms and its relevance to crucial physiological/pathological events

Abstract

The treatment of infections caused by fungi and trypanosomatids is difficult due to the eukaryotic nature of these microbial cells, which are similar in several biochemical and genetic aspects to host cells. Aggravating this scenario, very few antifungal and anti-trypanosomatidal agents are in clinical use and, therefore, therapy is limited by drug safety considerations and their narrow spectrum of activity, efficacy and resistance. The search for new bioactive agents against fungi and trypanosomatids has been expanded because progress in biochemistry and molecular biology has led to a better understanding of important and essential pathways in these microorganisms including nutrition, growth, proliferation, signaling, differentiation and death. In this context, proteolytic enzymes produced by these eukaryotic microorganisms are appointed and, in some cases, proven to be excellent targets for searching novel natural and/or synthetic pharmacological compounds, in order to cure or prevent invasive fungal/trypanosomatid diseases. With this task in mind, our research group and others have focused on aspartic-type proteases, since the activity of this class of hydrolytic enzymes is directly implicated in several facets of basic biological processes of both fungal and trypanosomatid cells as well as due to the participation in numerous events of interaction between these microorganisms and host structures. In the present paper, a concise revision of the beneficial effects of aspartic protease inhibitors, with emphasis on the aspartic protease inhibitors used in the anti-human immunodeficiency virus therapy, will be presented and discussed using our experience with the following microbial models: the yeast Candida albicans , the filamentous fungus Fonsecaea pedrosoi and the protozoan trypanosomatid Leishmania amazonensis .

Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction

“…Peptidases have emerged as potential targets to the development of new antifungal chemotherapeutics 9 . Several studies have shown that fungal aspartic peptidases are also sensitive to inhibitors produced against HIV used in highly active antiretroviral therapy 13,41,42 . Thus, the ability of these PIs to modulate essential events in fungal cells has been investigated 9,23 .…”

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

“…Sources of nitrogen and carbon affect both the constructive synthesis in cultures and the enzyme production [190,191]. Santos and co-workers [184] reported that C. albicans presented a high level of surface Sap1-3 antigens and a high amount of aspartic protease activity secreted into the extracellular environment when Fig.…”

A low-molecular-mass aspartic protease inhibitor from a novel Penicillium sp.: implications in combating fungal infections

“…Analysis of proteolytic enzymes of pathogenic micro-organisms might lead to the design of inhibitors to control these pathogens (Dos Santos, 2011). To colonize a host, fungal micro-organisms have evolved strategies to invade tissues, optimize growth and propagate.…”