期刊
ACS CHEMICAL BIOLOGY
卷 17, 期 1, 页码 118-128出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.1c00743
关键词
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资金
- National Science Foundation [ACI-1548562, CBET-1934284]
- National Institutes of Health [R01DK109559]
- North Carolina Biotechnology Center [2019-FLG-3841]
- UNC Center for Gastrointestinal Biology and Disease [P30DK034987]
In this study, promising toxin A-targeting peptides were identified using a computational strategy that integrates peptide binding design algorithm and molecular dynamics simulation. These peptides may serve as potential inhibitors against C. difficile infection. In vitro experiments showed that phage-display peptide RP and in silico peptide NPA exhibit strong toxin-neutralizing properties, while in silico peptide NPB has relatively lower efficacy against TcdA.
Clostridium difficile infection is mediated by two major exotoxins: toxins A (TcdA) and B (TcdB). Inhibiting the biocatalytic activities of these toxins with targeted peptide-based drugs can reduce the risk of C. difficile infection. In this work, we used a computational strategy that integrates a peptide binding design (PepBD) algorithm and explicit-solvent atomistic molecular dynamics simulation to determine promising toxin A-targeting peptides that can recognize and bind to the catalytic site of the TcdA glucosyltransferase domain (GTD). Our simulation results revealed that two out of three in silico discovered peptides, viz. the neutralizing peptides A (NPA) and B (NPB), exhibit lower binding free energies when bound to the TcdA GTD than the phage-display discovered peptide, viz. the reference peptide (RP). These peptides may serve as potential inhibitors against C. difficile infection. The efficacy of the peptides RP, NPA, and NPB to neutralize the cytopathic effects of TcdA was tested in vitro in human jejunum cells. Both phage-display peptide RP and in silico peptide NPA were found to exhibit strong toxin-neutralizing properties, thereby preventing the TcdA toxicity. However, the in silico peptide NPB demonstrates a relatively low efficacy against TcdA.
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