Universität zu Köln

Drexelius, Marco, Reinhardt, Andre, Grabeck, Joshua, Cronenberg, Tom, Nitsche, Frank ORCID: 0000-0003-3950-8285, Huesgen, Pitter ORCID: 0000-0002-0335-2242, Maier, Berenike ORCID: 0000-0001-6971-9927 and Neundorf, Ines (2021). Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity. Biochem. J., 478 (1). S. 63 - 79. LONDON: PORTLAND PRESS LTD. ISSN 1470-8728

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Abstract

Multidrug resistant (MDR) bacteria have adapted to most clinical antibiotics and are a growing threat to human health. One promising type of candidates for the everlasting demand of new antibiotic compounds constitute antimicrobial peptides (AMPs). These peptides act against different types of microbes by permeabilizing pathogen cell membranes, whereas being harmless to mammalian cells. Contrarily, another class of membrane-active peptides, namely cell-penetrating peptides (CPPs), is known to translocate in eukaryotic cells without substantially affecting the cell membrane. Since CPPs and AMPs share several physicochemical characteristics, we hypothesized if we can rationally direct the activity of a CPP towards antimicrobial activity. Herein, we describe the screening of a synthetic library, based on the CPP sC18, including structure-based design to identify the active residues within a CPP sequence and to discover novel AMPs with high activity. Peptides with increased hydrophobicity were tested against various bacterial strains, and hits were further optimized leading to four generations of peptides, with the last also comprising fluorinated amino acid building blocks. Interestingly, beside strong antibacterial activities, we also detected activity in cancer cells, while non-cancerous cells remained unharmed. The results highlight our new candidates, particularly those from generation 4, as a valuable and promising source for the development of future therapeutics with antibacterial activity and beyond.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Drexelius, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Grabeck, Joshua UNSPECIFIED UNSPECIFIED UNSPECIFIED Cronenberg, Tom UNSPECIFIED UNSPECIFIED UNSPECIFIED Nitsche, Frank UNSPECIFIED orcid.org/0000-0003-3950-8285 UNSPECIFIED Huesgen, Pitter UNSPECIFIED orcid.org/0000-0002-0335-2242 UNSPECIFIED Maier, Berenike UNSPECIFIED orcid.org/0000-0001-6971-9927 UNSPECIFIED Neundorf, Ines UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-568740
DOI:	10.1042/BCJ20200698
Journal or Publication Title:	Biochem. J.
Volume:	478
Number:	1
Page Range:	S. 63 - 79
Date:	2021
Publisher:	PORTLAND PRESS LTD
Place of Publication:	LONDON
ISSN:	1470-8728
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEASE STABILITY; MECHANISM; SEQUENCE; DESIGN; TRENDS; CHARGE Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/56874