The Secreted Aspartic Proteinases as a New Target in the Therapy of Candidiasis

Abstract

Secreted aspartic proteinases (Saps) are important virulence factors in different types of candidiasis caused by Candida albicans (C. albicans). The various isoenzymes are expected to fulfil different tasks during mucosal or disseminated infections. It could be shown that the introduction of the proteinase inhibitors like saquinavir and indinavir in the therapy of human immunodeficiency virus (HIV) infected patients has an effect on Sap activity in vitro as well as in vivo. Therefore, drugs like the HIV proteinase inhibitors could play an essential role in the treatment of candidiasis in the future, especially if further adapted to this target.

Synergistic combinations of antifungals and anti-virulence agents to fight againstCandida albicans

“…45 The HIV proteinase inhibitors, such as saquinavir and indinavir, which already showed potency in the cure of candidiasis, can be carefully selected and considered as potential candidates for anticandidal virulence agents. 46,47 Virulence Phospholipases are another major C. albicans secreted enzymes contributed to invasiveness during infections. Ganendren et al reported that phospholipases substrates analogues such as alexidine dihydrochloride and 1,12 bis-(tributylphosphonium)-dodecane dibromide had a relatively broad antifungal activity against C. albicans, Cryptococcus neoformans, Aspergillus flavus in vitro.…”

Candida and candidiasis in HIV-infected patients

“…In the absence of host cooperation, particularly with the large set of immune dysfunctions typical of HIV-infected patients, antifungal therapy remains ineffective in the long run. This fact has prompted the search for new approaches in anti-Candida drugs including Sap peptidomimetics inhibitors [122]. Some of these have shown appreciable activity in vitro and in a model of vaginal candidiasis in rats challenged by a fluconazole-resistant strain of C. albicans [123].…”

Incorporation of Nonnatural Amino Acids Into Proteins

“…This tRNA was also a competent suppressor tRNA in a rabbit reticulocyte in vitro translation system. 125 I-Tyr was incorporated specifically into position 9 of a 16 residue peptide (54).…”

“…New efforts in HIV protease inhibitor design are also targeting the challenge of drug resistance by introducing monocycles into peptides (123). Other examples whereby proteases are therapeutically targeted with nonnatural peptides or peptide mimetics include angiotensin-converting enzyme inhibitors (e.g., ramipril as a treatment for hypertension), the secretases (key proteases thought to be relevant to the emergence of Alzheimer's disease) (124), and the essential secreted aspartyl proteases from Candida albicans, as new antifungal targets (125,126).…”