Journal
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
Volume 6, Issue 4, Pages 402-413Publisher
KEAI PUBLISHING LTD
DOI: 10.1016/j.synbio.2021.11.004
Keywords
D-peptide; Web server; Evolutionary algorithm; Peptide design; Molecular docking; Mirror-image phage display
Categories
Funding
- High Performance and Cloud Computing Group at the Zentrum fur Datenverarbeitung of the University of Tubingen
- state of Baden-Wurttemberg through bwHPC
- German Research Foundation (Deutsche Forschungsgemeinschaft DFG) [INST 37/935-1 FUGG]
- CIBSS -Centre for Integrative Biological Signalling Studies/BIOSS -Centre for Biological Signalling Studies (University of Freiburg)
- Student deanery (Studiendekanat) Molecular Medicine (University of Freiburg)
- Integrated DNA Technologies (IDT)
- Maria Ladenburger Stiftung (Freiburg, Germany)
- Friends of the University of Freiburg
- OFAMED Open Student Council Medicine (Offene Fachschaft Medizin e. V.) -University of Freiburg
- Neue Universitatsstiftung Freiburg
- Abcam
- Geneious
- Institute for Biochemistry (University of Freiburg)
- Thorsten Hugel Group (University of Freiburg)
- BioCopy GmbH (Emmendingen, Germany)
- Hahn-Schickard Institute (Freiburg, Germany)
- Zahnarztpraxis Thomas Ruckes (Germany)
- Merck Millipore
- New England Biolabs GmbH
- Zymo Research
- Carl Roth GmbH + Co. KG (Germany)
- Eurofins Scientific
- Faust Lab Science GmbH (Germany)
- Macherey-Nagel (Germany)
- Jena Bioscience (Germany)
- NIPPON Genetics Europe (Germany)
- GENEWIZ Europe -A Brooks Life Sciences Company (Germany)
- Institute for Biology III (University of Freiburg)
- Sparkasse Freiburg Nordlicher Breisgau (Germany)
- Greiner Bio-One
- La Luna Baila
- Faculty of Biology
- Dr. Falk Pharma GmbH (Freiburg, Germany)
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The use of D-peptides, composed of dextrorotatory enantiomers, offers improved stability and efficacy in peptide therapeutics. The web server finDr allows for the computational identification and optimization of D-peptide ligands to any protein structure, providing a tool for predicting optimal binders. This approach facilitates D-peptide discovery in biotechnology and biomedicine, presenting a cost-effective and user-friendly alternative to conventional methods.
In the rapidly expanding field of peptide therapeutics, the short in vivo half-life of peptides represents a considerable limitation for drug action. D-peptides, consisting entirely of the dextrorotatory enantiomers of naturally occurring levorotatory amino acids (AAs), do not suffer from these shortcomings as they are intrinsically resistant to proteolytic degradation, resulting in a favourable pharmacokinetic profile. To experimentally identify D-peptide binders to interesting therapeutic targets, so-called mirror-image phage display is typically performed, whereby the target is synthesized in D-form and L-peptide binders are screened as in conventional phage display. This technique is extremely powerful, but it requires the synthesis of the target in D-form, which is challenging for large proteins. Here we present finDr, a novel web server for the computational identification and optimization of D-peptide ligands to any protein structure (https://findr.biologie.uni-freiburg.de/). finDr performs molecular docking to virtually screen a library of helical 12-mer peptides extracted from the RCSB Protein Data Bank (PDB) for their ability to bind to the target. In a separate, heuristic approach to search the chemical space of 12-mer peptides, finDr executes a customizable evolutionary algorithm (EA) for the de novo identification or optimization of D-peptide ligands. As a proof of principle, we demonstrate the validity of our approach to predict optimal binders to the pharmacologically relevant target phenol soluble modulin alpha 3 (PSM alpha 3), a toxin of methicillin-resistant Staphylococcus aureus (MRSA). We validate the predictions using in vitro binding assays, supporting the success of this approach. Compared to conventional methods, finDr provides a low cost and easy-to-use alternative for the identification of D-peptide ligands against protein targets of choice without size limitation. We believe finDr will facilitate D-peptide discovery with implications in biotechnology and biomedicine.
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