Structure-function-guided exploration of the antimicrobial peptide polybia-CP identifies activity determinants and generates synthetic therapeutic candidates
Name
s42003-018-0224-2.pdf
Description
Published version
Size
2.67 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Torres, Marcelo DT
Pedron, Cibele N
Higashikuni, Yasutomi
Kramer, Robin M
Cardoso, Marlon H
Oshiro, Karen GN
Franco, Octávio L
Silva Junior, Pedro I
Silva, Fernanda D
Oliveira Junior, Vani X
Date Issued
2018
Journal
Communications Biology
Publisher
Springer Nature
Version
Final published version
Abstract
© 2018, The Author(s). Antimicrobial peptides (AMPs) constitute promising alternatives to classical antibiotics for the treatment of drug-resistant infections, which are a rapidly emerging global health challenge. However, our understanding of the structure-function relationships of AMPs is limited, and we are just beginning to rationally engineer peptides in order to develop them as therapeutics. Here, we leverage a physicochemical-guided peptide design strategy to identify specific functional hotspots in the wasp-derived AMP polybia-CP and turn this toxic peptide into a viable antimicrobial. Helical fraction, hydrophobicity, and hydrophobic moment are identified as key structural and physicochemical determinants of antimicrobial activity, utilized in combination with rational engineering to generate synthetic AMPs with therapeutic activity in a mouse model. We demonstrate that, by tuning these physicochemical parameters, it is possible to design nontoxic synthetic peptides with enhanced sub-micromolar antimicrobial potency in vitro and anti-infective activity in vivo. We present a physicochemical-guided rational design strategy to generate peptide antibiotics.
MIT Department
Massachusetts Institute of Technology. Synthetic Biology Center
Massachusetts Institute of Technology. Center for Microbiome Informatics and Therapeutics
Massachusetts Institute of Technology. Research Laboratory of Electronics
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Division of Comparative Medicine
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S42003-018-0224-2
