Fungal Aspartic Proteases as Possible Therapeutic Targets

Monod, Michel; Staib, Peter; Reichard, Utz; Jousson, Olivier

doi:10.1002/9783527630943.ch20

Cited by 5 publications

(12 citation statements)

References 147 publications

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“…Mature fungal secreted proteases serve the important functions of breaking down proteinaceous material, splitting large peptides into assailable material for nutrition and for colonization and evading the immune system of the host (Behnsen et al, 2010;Monod et al, 2009). Such key features for the biology and pathology of fungi make secreted proteases potential candidates for therapeutic intervention (Monod et al, 2010;Yike, 2011). The impact of structural knowledge on the discovery of drugs targeting proteases from different classes and the availability of benchmark metallopeptidases such as thermolysin in identifying and characterizing new generations of molecules (Castro et al, 2011;Cudic & Fields, 2009;Deu et al, 2012;Englert et al, 2010;Ferná ndez et al, 2010;Mittl & Grü tter, 2006) have been recognized on numerous occasions.…”

Section: Figurementioning

confidence: 99%

A functional and structural study of the major metalloprotease secreted by the pathogenic fungusAspergillus fumigatus

Fernández¹,

Russi²,

Vendrell³

et al. 2013

Acta Crystallogr D Biol Crystallogr

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Fungalysins are secreted fungal peptidases with the ability to degrade the extracellular matrix proteins elastin and collagen and are thought to act as virulence factors in diseases caused by fungi. Fungalysins constitute a unique family among zinc-dependent peptidases that bears low sequence similarity to known bacterial peptidases of the thermolysin family. The crystal structure of the archetype of the fungalysin family, Aspergillus fumigatus metalloprotease (AfuMep), has been obtained for the first time. The 1.8 Å resolution structure of AfuMep corresponds to that of an autoproteolyzed proenzyme with separate polypeptide chains corresponding to the N-terminal prodomain in a binary complex with the C-terminal zinc-bound catalytic domain. The prodomain consists of a tandem of cystatin-like folds whose C-terminal end is buried into the active-site cleft of the catalytic domain. The catalytic domain harbouring the key catalytic zinc ion and its ligands, two histidines and one glutamic acid, undergoes a conspicuous rearrangement of its N-terminal end during maturation. One key positively charged amino-acid residue and the C-terminal disulfide bridge appear to contribute to its structural-functional properties. Thus, structural, biophysical and biochemical analysis were combined to provide a deeper comprehension of the underlying properties of A. fumigatus fungalysin, serving as a framework for the as yet poorly known metallopeptidases from pathogenic fungi.

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Section: Figurementioning

confidence: 99%

A functional and structural study of the major metalloprotease secreted by the pathogenic fungusAspergillus fumigatus

Fernández¹,

Russi²,

Vendrell³

et al. 2013

Acta Crystallogr D Biol Crystallogr

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“…Mortality rates from serious systemic candidiasis are high. Contributing to the invasion process that leads to systemic infection are a number of virulence factors, among which the secreted aspartic proteases (Saps) are well documented (3,4). C. albicans possesses a family of 10 Saps, in which Saps 1-3 and Saps 4 -6 are two closely related subfamilies (3).…”

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confidence: 99%

Candida albicanssecreted aspartic proteases 4–6 induce apoptosis of epithelial cells by a novel Trojan horse mechanism

Downs

Ghosh³

et al. 2013

FASEB j.

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Systemic infection by the pathogenic yeast Candida albicans produces high mortality in immune-compromised people. Such infection starts with the penetration of the organism at the mucosal surfaces, facilitated by the secreted aspartic proteases (Saps) 4, 5, and 6. The functional mechanism of these virulence factors is unclear. We discovered that Saps 4-6 each contains amino acid motifs RGD/KGD to bind integrins on epithelial cell A549 and are internalized to endosomes and lysosomes. These processes are inhibited by RGD-containing peptides or by substituting RGD motifs of these Saps. The internalization of Saps 4-6 results in partial permeabilization of lysosomal membranes, measured by the redistribution of the lysosomal tropic dye acridine orange to the cytosol, and the triggering of apoptosis via caspase activation. Sap 2 and mutated Saps 4-6 contain no RGD motif, are ineffective in these processes, and a proteolytic inhibitor abolished Sap 4 activity in lysosome permeabilization. Same results were also seen for human tongue keratinocyte SCC-15 cells. Mucosal lesions from this fundamental new mechanism may permit C. albicans to enter the body and may be used to attack cells in immune defense during systemic infections. RGD-motif may also be incorporated in Sap inhibitors for Candidiasis drugs targeting to lysosomes.

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“…C. albicans can cause infections in humans by (a) epithelial adhesion in the yeast form, (b) yeast-hyphae transition and epithelial penetration, and (c) dissemination and infection [22,23]. Candida species may also cause the biofilm formation in medical devices and implants of patients [6].…”

Section: Introductionmentioning

confidence: 99%

Novel Antifungal Mechanism of Resveratrol: Apoptosis Inducer in Candida albicans

Lee

2014

Curr Microbiol

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Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a well-known natural polyphenolic compound that has garnered considerable interest because of its bioavailability and pharmacokinetics in humans. Although the antimicrobial activity of resveratrol has recently been focused, however, the antifungal activity and its mechanism are still largely unknown. Here, we report for the first time the potential of resveratrol as an apoptosis inducer in the human pathogenic fungus Candida albicans. The results showed that resveratrol exerted its effects from the early to the late stages of apoptosis and involved the activity of reactive oxygen species, particularly hydroxyl radicals ((∙)OH). DiOC6(3) and JC-1 staining indicated that loss of mitochondrial membrane potential (ΔΨ m) is a key event in resveratrol-induced apoptosis. Finally, we investigated metacaspase activation resulting from mitochondrial dysfunction. The result showed that resveratrol strongly activated metacaspase and promoted cytochrome c release. In summary, resveratrol induces fungal apoptosis through a caspase-dependent mitochondrial pathway and is a potential agent for treating human fungal diseases.

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Fungal Aspartic Proteases as Possible Therapeutic Targets

Cited by 5 publications

References 147 publications

A functional and structural study of the major metalloprotease secreted by the pathogenic fungusAspergillus fumigatus

A functional and structural study of the major metalloprotease secreted by the pathogenic fungusAspergillus fumigatus

Candida albicanssecreted aspartic proteases 4–6 induce apoptosis of epithelial cells by a novel Trojan horse mechanism

Novel Antifungal Mechanism of Resveratrol: Apoptosis Inducer in Candida albicans

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