The Structural Biology and Critical Evaluation of Bacterial Proteases as Targets in New Drug Design

TL;DR

This study analyzes bacterial proteases, especially Salmonella PgtE, and their similarities to human MMPs to inform the design of targeted prodrug carriers for bacterial infections and cancer metastasis.

Contribution

It provides a detailed bioinformatics analysis of bacterial proteases and MMPs, identifying substrate similarities to aid drug design against bacterial infections and cancer.

Findings

PgtE protease acts on pro-MMP-9, indicating potential for targeted drug delivery.

Shared substrate motifs between bacterial proteases and MMPs were identified.

Bioinformatics tools revealed conserved regions and binding sites relevant for drug targeting.

Abstract

Bacteria produce a range of proteolytic enzymes, for which a number human equivalent or structurally similar examples exist and the primary focus of this study was to analyse the published literature to find proteolytic enzymes, specifically endoproteses and to examine the similarity in the substrates that they act on so as to predict a suitable structural motif which can be used as the basis for preparation of useful prodrug carriers against diseases caused by specific bacteria like Salmonella. Also, the similarities between the bacterial proteases and the action of human matrix metalloproteinases (MMPs), together with the MMP-like activity of bacterial endoproteases to activate human MMPs, were also analysed. This information was used to try to identify substrates on which the MMPs and bacterial proteases act, to aid the design of oligopeptide prodrug carriers to treat cancer and its metastatic spread. MMPs are greatly involved in cancer growth and progression, a few MMPs and certain proteases share a similar type of activity in degrading the extra cellular matrix (ECM) and substrates including gelatin. Our primary targets of study were to identify the proteases and MMPs that facilitate the migration of bacteria and growth of tumour cells respectively. The study was thus a two-way approach to study the substrate specificity of both bacterial proteases and MMPs, thereby to help in characterisation of their substrates. Various bioinformatics tools were used in the characterisation of the proteases and substrates as well as in the identification of possible binding sites and conserved regions in a range of candidate proteins. Central to this project was the salmonella derived PgtE surface protease that has been shown recently to act upon the pro-forms of human MMP-9.