Aspartic Peptidase Inhibitors: Implications in Drug Development

Abstract

The last decade has witnessed an effervescence of research interest in the development of potent inhibitors of various aspartic peptidases. As an enzyme family, aspartic peptidases are relatively a small group that has received enormous interest because of their significant roles in human diseases like involvement of renin in hypertension, cathepsin D in metastasis of breast cancer, beta-Secretase in Alzheimer's Disease, plasmepsins in malaria, HIV-1 peptidase in acquired immune deficiency syndrome, and secreted aspartic peptidases in candidal infections. There have been developments on clinically active inhibitors of HIV-1 peptidase, which have been licensed for the treatment of AIDS. The inhibitors of plasmepsins and renin are considered a viable therapeutic strategy for the treatment of malaria and hypertension. Relatively few inhibitors of cathepsin D have been reported, partly because of its uncertain role as a viable target for therapeutic intervention. The beta-secretase inhibitors OM99-2 and OM003 were designed based on the substrate specificity information. The present article is a comprehensive state-of-the-art review describing the aspartic peptidase inhibitors illustrating the recent developments in the area. In addition, the homologies between the reported inhibitor sequences have been analyzed. The understanding of the structure-function relationships of aspartic peptidases and inhibitors will have a direct impact on the design of new inhibitor drugs.

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] .…”

“…The possibility of aspartic protease inhibitors binding to or interfere with other molecules than aspartic proteases can not be excluded [35] . In this context, these compounds can generate irreversible toxic effects by perturbing the homeostasis of the microbial cells, culminating in death of microorganisms.…”

“…Actually, C. albicans possesses ten different SAP genes (SAP1 to SAP10), which are expressed according to distinct environments and host conditions [56][57][58][59][60] . Therefore, Saps are potential targets for the development of novel anti-C. albicans drugs [1,2,34,35] . In this context, several groups have demonstrated that aspartic protease inhibitors, including pepstatin A and the first generation of protease inhibitors used in anti-human immunodeficiency virus (HIV) therapy (nelfinavir, saquinavir, ritonavir and indinavir), are able to restrain Sap activity (especially Sap1, Sap2 and Sap3) as well as arrest crucial events of C. albicans yeast cells such as proliferation and adhesion to both abiotic (e.g.…”

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

“…Extracellular proteases of eukaryotic microbial pathogens have received tremendous research interest as potential drug targets for pharmaceutical intervention (Dash et al, 2003;Dos Santos, 2010). Analysis of proteolytic enzymes of pathogenic micro-organisms might lead to the design of inhibitors to control these pathogens (Dos Santos, 2011).…”

“…Aspartic proteases are a relatively small group of proteolytic enzymes. Over the last decade, they have received tremendous research interest as potential targets for pharmaceutical intervention, as many have been shown to play significant roles in physiological and pathological processes (Dash et al, 2003). Study of the kinetic properties of this class of enzymes has been motivated by their pharmaceutical and commercial importance, and has evoked considerable interest regarding the role of their inhibitors.…”