Aspartic Proteolytic Inhibitors Induce Cellular and Biochemical Alterations in Fungal Cells

Abstract

Although fungal infections contribute substantially to human morbidity and mortality, the impact of these diseases on human health is not widely appreciated. Diagnosis and treatment of fungal infections remain a challenge in medicine despite recent major advances. The search for novel pharmacological compounds with antifungal action is a real requirement. Taking it into consideration, research groups have investigated the effects of aspartic peptidase inhibitors (PIs) on the development of human fungal pathogens such as Candida spp, mainly Candida albicans and Candida parapsilosis , Cryptococcus neoformans , Pneumocystis jiroveci and Fonsecaea pedrosoi , based on the following premises: (1) this class of hydrolytic enzymes performs multiple relevant roles in pathophysiological events associated to the fungal infections and (2) the introduction of human immunodeficiency virus (HIV) PIs in the clinical arena drastically reduced the opportunistic infections caused by fungi in this population. As expected, the blockage of one of these physiological/pathological processes should help in containing the fungal infection. Corroborating this hypothesis, both in vitro and in vivo studies have reported that classical aspartic PIs (e.g., pepstatin A) as well as HIV PIs (e.g., nelfinavir, saquinavir, ritonavir, indinavir, amprenavir, lopinavir and tipranavir) have induced several cellular and biochemical alterations on fungal cells. Some of the metabolic perturbations are extremely drastic to the fungal cells, which culminate in arresting nutrition, growth, proliferation, differentiation, adhesion, invasion and dissemination. In the present chapter, we will describe the beneficial effects of aspartic PIs against some human fungal pathogens, reporting in details their mechanisms capable in disturbing the fungal homeostasis.