The Impact of Lung Proteases on Snake-Derived Antimicrobial Peptides

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.

Review of the British Thoracic Society Winter Meeting 2021, 24–26 November 2021

“…Lung epithelial cells have been shown to be necessary effectors of inducible resistance7 and neutrophils are rich sources of AMPs. Furthermore, several other host factors such as pH, salt, mucins and host proteases are determinants of AMP activity 8 9. Reduced AMP activity against bacterial infection is seen in chronic obstructive pulmonary disease (COPD) and with cigarette smoke exposure 10.…”