Barrel Assemblies of Membrane Active Artificial Foldamers

Projektinformationen

BARREL

ID Finanzhilfevereinbarung: 660030

DOI

10.3030/660030

Projekt abgeschlossen

EK-Unterschriftsdatum 25 März 2015

Startdatum 1 August 2015

Enddatum 31 Juli 2017

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 146 239,20

EU-Beitrag

€ 146 239,20

Koordiniert durch

HUN-REN TERMESZETTUDOMANYI KUTATOKOZPONT
Hungary

Periodic Reporting for period 1 - BARREL (Barrel Assemblies of Membrane Active Artificial Foldamers)

Berichtszeitraum: 2015-08-01 bis 2017-07-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The sharp increase of microbial resistance against antibiotics is a global health threat, which have induced intensive research on antimicrobial agents. As persistent cells often become slow-growing or dormant, strategies targeting their membrane are becoming more relevant. In this respect, artificial assemblies of compounds with membrane activity and antimicrobial potential are thus highly interesting as potential new set of antibiotic agents. Considering that natural peptides with membrane activity are present in the innate immune system without resistance developed against them, these are interesting for development of novel antimicrobial compounds. Note, however, that bioavailability of these compounds is limited due to their sensitivity against degrading enzymes. Consequently, in recent decades an exponentially growing scientific interest is observed for peptidomimetic foldamers, which are peptide-based artificial compounds with structural diversity and folding properties often matching those of natural peptides. The membrane properties of these compounds however, is still poorly understood, therefore in the present proposal I aimed to develop and investigate non-natural foldamers that are capable of interacting with the lipid bilayer. Under the project period we have developed foldamers which readily interact with model membranes but at the same time are water soluble. Biophysical measurements also indicate, that these compounds oligomerize into preferentially beta-sheet rich assemblies, but do not form infinite fibrils. Based on these results we hope that this construct can be used in the future to develop novel non-natural species with antimicrobial potential.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

To provide new directions for development of antimicrobial compounds, during the project period I have investigated the structural and mechanistic properties of both natural and non-natural peptide derivatives addressing also their assembling properties upon interacting with lipid bilayers or other biologically relevant molecules. I have also reviewed the potential applicability of certain non-natural compounds in design of novel artificial biomolecules. These investigations have resulted in inducable structural properties for natural antimicrobial peptides, and in a set of membrane active sequences in the case of non-natural peptidic foldamers. Some of these results were already published in scientific journals publicly available. After completion of the project period we aim to further develop these foldamers in order to achieve self-assembling compounds that are selective against membranes of specific organisms and thus may serve as basis for future development of antimicrobials.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

It is hoped that by better understanding the above set of biomolecules we will arrive in the future to improved antimicrobial compounds efficiently addressing drug resistant microbes. Assembling properties of the compounds investigated may potentially be a key phenomenon in this regard. When assembled, these scaffolds may be too large for the target organism to exclude them from their membrane by their defense mechanisms. Although these results are achieved at the basic science level, these are hoped to be employed in more focused projects as initial basis for development of similar compounds. Providing knowledge for these developments is critical as in the next decades the global threat of antibiotic resistance by microbes could easily be the cause for death of several million people per year. According to recent reports by the World Health Organization (WHO), by 2050 antibiotic resistance could result in loss of more than 10 000 000 human lives per year. Consequently the project performed currently have a great potential impact on the future health and well-being of our society.

Schematic illustration on potential mechanisms of membrane active peptidic compounds