In Silico Structural Evaluation of Short Cationic Antimicrobial Peptides.

Ilaria Passarini,Sharon Rossiter,Mire Zloh,John Malkinson

doi:10.3390/pharmaceutics10030072

Ilaria Passarini, Sharon Rossiter + Show 2 more

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https://doi.org/10.3390/pharmaceutics10030072

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Abstract

Cationic peptides with antimicrobial properties are ubiquitous in nature and have been studied for many years in an attempt to design novel antibiotics. However, very few molecules are used in the clinic so far, sometimes due to their complexity but, mostly, as a consequence of the unfavorable pharmacokinetic profile associated with peptides. The aim of this work is to investigate cationic peptides in order to identify common structural features which could be useful for the design of small peptides or peptido-mimetics with improved drug-like properties and activity against Gram negative bacteria. Two sets of cationic peptides (AMPs) with known antimicrobial activity have been investigated. The first reference set comprised molecules with experimentally-known conformations available in the protein databank (PDB), and the second one was composed of short peptides active against Gram negative bacteria but with no significant structural information available. The predicted structures of the peptides from the first set were in excellent agreement with those experimentally-observed, which allowed analysis of the structural features of the second group using computationally-derived conformations. The peptide conformations, either experimentally available or predicted, were clustered in an “all vs. all” fashion and the most populated clusters were then analyzed. It was confirmed that these peptides tend to assume an amphipathic conformation regardless of the environment. It was also observed that positively-charged amino acid residues can often be found next to aromatic residues. Finally, a protocol was evaluated for the investigation of the behavior of short cationic peptides in the presence of a membrane-like environment such as dodecylphosphocholine (DPC) micelles. The results presented herein introduce a promising approach to inform the design of novel short peptides with a potential antimicrobial activity.

Highlights

The surge of multidrug resistant microorganisms and the lack of new antibiotics present a major challenge to modern medicine [1]
Three pathways are usually followed in efforts to obtain novel peptides: modification of existing templates through bioinformatics methods, often looking at the modification of the primary sequences; biophysical modelling, such as molecular dynamics simulations, which can take into account the effect of the environment on the conformations; and screening of libraries which may focus on the structure activity relationship (SAR) [6,7]
A set of 117 protein databank (PDB) entries corresponding to NMR-derived conformations of antimicrobial peptides was created (Table S1)

Summary

Introduction

The surge of multidrug resistant microorganisms and the lack of new antibiotics present a major challenge to modern medicine [1]. Naturally-occurring cationic peptides often possess antimicrobial properties [2] and represent a promising class of lead compounds to be selected for the design of new antibiotics. Of the nearly 5000 cationic antimicrobial peptides (AMPs) described to date, fewer than 100 are currently undergoing clinical trials [3], possibly due to the challenges related to the development of protein-based drugs. Several resources are available for predicting the 3D conformations of peptides, such as the online software PEP-FOLD [4], as well as their antimicrobial potential [5]. Three pathways are usually followed in efforts to obtain novel peptides: modification of existing templates through bioinformatics methods, often looking at the modification of the primary sequences; biophysical modelling, such as molecular dynamics simulations, which can take into account the effect of the environment on the conformations; and screening of libraries which may focus on the structure activity relationship (SAR) [6,7]. The complexity of problems associated with in vivo application of these molecules and understanding their mechanism of action calls for a continuous improvement of these methods, with the aim to obtain antimicrobial agents with improved pharmacological profiles

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