Bldesin, the first functionally characterized pathogenic fungus defensin with Kv1.3 channel and chymotrypsin inhibitory activities

Luo, Xudong; Zhu, Weihua; Ye, Xiangdong; Gao, Huanhuan; Tai, Xuejiao; Wu, Zheng; Qian, Yi; Ruan, Xiuhang; Li, Jian; Li, Shan; Chen, Zongyun

doi:10.1002/jbt.22244

Cited by 12 publications

(7 citation statements)

References 44 publications

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“…For example, metabolites or small molecules from fungus, Aspergillus fumigatus has anti-cancer potential; these small molecules are responsible for pathogenicity as well as the virulence nature of the fungus, A. fumugatus [ 16 ]. Previous reports [ 17 , 18 ] indicate that pathogenic fungus-derived virulence factors and the venom of numerous species including bees, snakes, scorpions and plant-derived toxins have significant anti-cancer activities. In line with this context, we hypothesized that the CBD protein-derived PS14 peptide could have significant anti-cancer potential.…”

Section: Resultsmentioning

confidence: 99%

Anti-Cancer and Anti-Inflammatory Activities of a Short Molecule, PS14 Derived from the Virulent Cellulose Binding Domain of Aphanomyces invadans, on Human Laryngeal Epithelial Cells and an In Vivo Zebrafish Embryo Model

et al. 2022

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In this study, the anti-cancer and anti-inflammatory activities of PS14, a short peptide derived from the cellulase binding domain of pathogenic fungus, Aphanomyces invadans, have been evaluated, in vitro and in vivo. Bioinformatics analysis of PS14 revealed the physicochemical properties and the web-based predictions, which indicate that PS14 is non-toxic, and it has the potential to elicit anti-cancer and anti-inflammatory activities. These in silico results were experimentally validated through in vitro (L6 or Hep-2 cells) and in vivo (zebrafish embryo or larvae) models. Experimental results showed that PS14 is non-toxic in L6 cells and the zebrafish embryo, and it elicits an antitumor effect Hep-2 cells and zebrafish embryos. Anticancer activity assays, in terms of MTT, trypan blue and LDH assays, showed a dose-dependent inhibitory effect on cell proliferation. Moreover, in the epithelial cancer cells and zebrafish embryos, the peptide challenge (i) caused significant changes in the cytomorphology and induced apoptosis; (ii) triggered ROS generation; and (iii) showed a significant up-regulation of anti-cancer genes including BAX, Caspase 3, Caspase 9 and down-regulation of Bcl-2, in vitro. The anti-inflammatory activity of PS14 was observed in the cell-free in vitro assays for the inhibition of proteinase and lipoxygenase, and heat-induced hemolysis and hypotonicity-induced hemolysis. Together, this study has identified that PS14 has anti-cancer and anti-inflammatory activities, while being non-toxic, in vitro and in vivo. Future experiments can focus on the clinical or pharmacodynamics aspects of PS14.

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Section: Resultsmentioning

confidence: 99%

Anti-Cancer and Anti-Inflammatory Activities of a Short Molecule, PS14 Derived from the Virulent Cellulose Binding Domain of Aphanomyces invadans, on Human Laryngeal Epithelial Cells and an In Vivo Zebrafish Embryo Model

et al. 2022

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“…Remarkably, a potassium channel inhibitory activity could be revealed for the N-terminal one, Purlisin-NT. Fungal defensins targeting voltage gated Kv1.3 channels have been described before (Xiang et al, 2015;Luo et al, 2019), and considering the high degree of conservation between Purlisin-NT and AfusinN, the latter might be one of those as well. Such channels are expressed in numerous human cells, among them macrophages and T lymphocytes in which they are involved in cell proliferation and activation as well as cytokine production (reviewed by Feske et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The infectious propagules of Aspergillus fumigatus are coated with antimicrobial peptides

Dümig

Binder

Gaculenko

et al. 2021

Cellular Microbiology

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Fungal spores are unique cells that mediate dispersal and survival in the environment. For pathogenic fungi encountering a susceptible host, these specialised structures may serve as infectious particles. The main causative agent of the opportunistic disease aspergillosis, Aspergillus fumigatus, produces asexual spores, the conidia, that become dissipated by air flows or water currents but also serve as propagules to infect a susceptible host. We demonstrate that the defX gene of this mould encodes putative antimicrobial peptides resembling cysteine‐stabilised (CS)αβ defensins that are expressed in a specific spatial and temporal manner in the course of asexual spore formation. Localisation studies on strains expressing a fluorescent proxy or tagged defX alleles expose that these antimicrobial peptides are secreted to coat the conidial surface. Deletion mutants reveal that the spore‐associated defX gene products delay the growth of Gram‐positive Staphylococcus aureus and demonstrate that the defX gene and presumably its encoded spore‐associated defensins confer a growth advantage to the fungal opponent over bacterial competitors. These findings have implications with respect to the ecological niche of A. fumigatus that serves as a ‘virulence school’ for this human pathogenic mould; further relevance is given for the infectious process resulting in aspergillosis, considering competition with the host microbiome or co‐infecting microorganisms to break colonisation resistance at host surfaces.

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“…A small number of fungal-derived defensins, such as plectasin and bldesin, possessed dual or multiple biological effects. 6,45,46 But unlike them, purlisin achieved different functions by dividing itself into two separate molecules. The purlisin-NT has a strong inhibitory effect on hKv1.3 potassium channel like animal-toxin and extremely weak antibacterial activity.…”

Section: Discussionmentioning

confidence: 99%

“…The biological effect studies have revealed that purlisin was a bifunctional molecule coupled with antimicrobial and potassium channel blocking activities. A small number of fungal‐derived defensins, such as plectasin and bldesin, possessed dual or multiple biological effects 6,45,46 . But unlike them, purlisin achieved different functions by dividing itself into two separate molecules.…”

Section: Discussionmentioning

confidence: 99%

Purlisin, a toxin‐like defensin derived from clinical pathogenic fungus Purpureocillium lilacinum with both antimicrobial and potassium channel inhibitory activities

Shen

Cao

et al. 2020

The FASEB Journal

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Clinical fungal infections always cause a negative impact on human health. Moreover, during the interaction of pathogenic fungi with the environment and host, many biologically active substances are produced. Here, we report a new toxin-like defensin of purlisin derived from a clinical pathogenic isolate of Purpureocillium lilacinum. The analysis of its genomic and mRNA sequences revealed an open reading frame of 444 bp without introns. The deduced precursor peptide was composed of 147 amino acids, and the mature peptide were identified at protein level by LC-ESI-Q-TOF-MS/ MS. After posttranslational processing, the precursor peptide of purlisin was split into two independent peptides. The two mature defensins, purlisin-NT and purlisin-CT, are consisting of 36 and 38 amino acid residues, which can form three and four intramolecular disulfide bonds, respectively. The results of circular dichroism and homology modeling revealed that they adopted a representative cysteine-stabilized α-helical and β-sheet motif. The purlisin-NT showed a dose-dependent selective inhibition of immune-related hKv1.3 target channel with IC 50 value of 0.2 ± 0.04 μM but no obvious antibacterial activity, while the purlisin-CT displayed antimicrobial activities against gram-positive bacteria as well as clinical isolates of MRSA and low affinities for potassium channels. Our findings suggest that purlisin-NT with immunosuppressive effects and purlisin-CT possessing antibacterial activities are adapted to the survival and pathogenicity of clinical P lilacinumis. Moreover, they can also be used as templates for the design of novel antibacterial peptide and immunosuppressive agents.

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Bldesin, the first functionally characterized pathogenic fungus defensin with Kv1.3 channel and chymotrypsin inhibitory activities

Cited by 12 publications

References 44 publications

Anti-Cancer and Anti-Inflammatory Activities of a Short Molecule, PS14 Derived from the Virulent Cellulose Binding Domain of Aphanomyces invadans, on Human Laryngeal Epithelial Cells and an In Vivo Zebrafish Embryo Model

Anti-Cancer and Anti-Inflammatory Activities of a Short Molecule, PS14 Derived from the Virulent Cellulose Binding Domain of Aphanomyces invadans, on Human Laryngeal Epithelial Cells and an In Vivo Zebrafish Embryo Model

The infectious propagules of Aspergillus fumigatus are coated with antimicrobial peptides

Purlisin, a toxin‐like defensin derived from clinical pathogenic fungus Purpureocillium lilacinum with both antimicrobial and potassium channel inhibitory activities

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