The Impact of Lung Proteases on Snake-Derived Antimicrobial Peptides.

Shannice E Creane,Sinéad Weldon,John P Dalton,Clifford C Taggart,Damian Downey,Simon R Carlile

doi:10.3390/biom11081106

Shannice E Creane, Sinéad Weldon + Show 4 more

Open Access

https://doi.org/10.3390/biom11081106

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Abstract

Respiratory infections are a leading cause of global morbidity and mortality and are of significant concern for individuals with chronic inflammatory lung diseases. There is an urgent need for novel antimicrobials. Antimicrobial peptides (AMPs) are naturally occurring innate immune response peptides with therapeutic potential. However, therapeutic development has been hindered by issues with stability and cytotoxicity. Availing of direct drug delivery to the affected site, for example the lung, can reduce unwanted systemic side effects and lower the required dose. As cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) lungs typically exhibit elevated protease levels, the aim of this study was to assess their impact on snake-derived AMPs. Peptide cleavage was determined using SDS-PAGE and antimicrobial and anti-inflammatory activities of neutrophil elastase (NE)-incubated peptides were assessed using a radial diffusion assay (RDA) and an in vitro LPS-induced inflammation model, respectively. Although the snake-derived AMPs were found to be susceptible to cleavage by lung proteases including NE, several retained their function following NE-incubation. This facilitated the design of novel truncated derivatives that retained functionality following NE incubation. Snake-derived AMPs are tractable candidate treatments for use in environments that feature elevated NE levels, such as the CF airways.

Highlights

The impact of lung proteases on snake-derived Antimicrobial peptides (AMPs) was assessed and we show that despite these AMPs being susceptible to protease degradation, several fragments still retained their antimicrobial activity which allowed the design of smaller stable derivative peptides
The molecular weight (Da), net charge, hydrophobic moment and Grand Average of Hydropathicity (GRAVY) value of the peptides used in this study were predicted using ExPASy Bioinformatics Resource Portal Protparam software (Swiss Institute of Bioinformatics, Lausanne, Switzerland) available at https://web.expasy.org/protparam/
Individuals with chronic inflammatory lung diseases are more susceptible to infection, with up to 95% of cystic fibrosis (CF) patients succumbing to chronic lung infection [2]