Aspartic Peptidase Inhibitors as Potential Bioactive Pharmacological Compounds Against Human Fungal Pathogens

Abstract

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 resistant fungal strains. In view of this, a number of new strategies to obstruct fungal biological processes have emerged; one of them is focused on peptidase inhibition. This particular class of hydrolytic enzymes cleaves peptide bond in proteinaceous substrates, a reaction extremely important in maintaining the physiology of all living cells. Interestingly, peptidases are also essential virulence factors for prokaryotic and eukaryote micro-organisms, including fungi, during all stages of the infection process. Consequently, peptidases are potential targets for the development of future antifungal drugs. This chapter will focus on the potential use of aspartic peptidase inhibitors against human fungal pathogens, showing the capability of these bioactive pharmacological compounds to arrest vital fungal processes such as growth, differentiation, nutrition, and interaction with host components.

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

“…Currently, the main approach has been to obtain good inhibitors of the target protease, in the belief that inhibition of the activity will be therapeutic. In this context, our research group has published some works that corroborate this premise [1][2][3][4][5][6]10,[29][30][31][32][33][34][35][36][37][38][39] .…”

“…Collectively, proteases participate in different steps of the multifaceted interaction events between microorganism and host structures, being considered as virulent attributes. Consequently, the biochemical characterization of these proteolytic enzymes is of interest not only for understanding proteases in general but also for understanding their roles in microbial infections and thus their exploitation as targets for rational chemotherapy of microbial diseases [3,6,10,[18][19][20][21][22][23][24] .…”

“…I am a peer reviewer for international scientific journals, as well as career and research grant committees. In addition, I have accepted invitations to write reviews and book chapters on the themes: (1) relevance of proteolytic enzymes produced by microorganisms; and (2) antimicrobial properties of protease inhibitors [1][2][3][4][5][6][7][8][9][10][11] . Over the last years, my group has focused on the identification, biochemical characterization and discovery of biological functions of proteases produced by microorganisms, with emphasis in trypanosomatids and fungi ( Figure 3).…”

Molecular and Proteolytic Profiles of Trypanosoma cruzi Sylvatic Isolates from Rio de Janeiro-Brazil

“…Collectively, proteases participate in different steps of the multifaceted interaction events between microorganism and host structures, being considered as virulent attributes. Consequently, the biochemical characterization of these proteolytic enzymes is of interest not only for understanding proteases in general, but also for understanding their roles in microbial infections, and thus, their use as targets for rational chemotherapy of microbial diseases (Santos, 2010) (dos Santos, 2011.…”

“…Similarly, endopeptidases are classified according to essential catalytic residues at their active sites in: serine, metallo, glutamic, threonine, cysteine and aspartic endopeptidases. Conversely, there are a few miscellaneous proteases that do not precisely fit into the standard classification (dos Santos, 2010Santos, , 2011.…”