Improving the Selectivity of Antimicrobial Peptides from Anuran Skin
| Autor: | Juraj Simunić, Julie Vasseur, Ali Ladram, Viktor Bojović, Damir Vukičević, Nédia Kamech, Christophe Piesse, Davor Juretić |
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| Přispěvatelé: | Biosynthèse des Signaux Peptidiques [IBPS] (IBPS-BIOSIPE), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines, PCR, Interaction Moléculaires [IBPS] (IBPS-IPIM), Croatian Ministry of Science, Education and Sports [177-1770495-0476, 177-0000000-0884, 037-0000000-2779, 098-1770495-2919] |
| Rok vydání: | 2012 |
| Předmět: |
[SDV]Life Sciences [q-bio]
General Chemical Engineering Antimicrobial peptides Peptide Xenopus Proteins Library and Information Sciences Hemolysis Protein Structure Secondary Structure-Activity Relationship Minimum inhibitory concentration Therapeutic index Protein structure Drug Discovery Animals Structure–activity relationship Skin chemistry.chemical_classification Internet Bacteria biology Circular Dichroism General Chemistry biology.organism_classification antimicrobial peptides peptide software drug design anura ascaphin-8 XT-7 Computer Science Applications Biochemistry chemistry Anura Antibacterial activity Oligopeptides Software Antimicrobial Cationic Peptides |
| Zdroj: | Journal of Chemical Information and Modeling Journal of Chemical Information and Modeling, 2012, 52 (12), pp.3341-3351. ⟨10.1021/ci300328y⟩ |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/ci300328y |
| Popis: | International audience; Anuran skin is known to be a rich source of antimicrobial peptides although their therapeutic potential is often limited due to their toxicity against mammalian cells. The analysis of structure-activity relationships among anuran antimicrobial peptides provided the parameters to construct the Mutator tool for improving their selectivity for bacterial cells, by suggesting appropriate point substitutions. Double substitution analogues [K2, K16] of the Xenopus tropicalis peptide XT-7 and [I2, K19] of the Ascaphus truei peptide ascaphin-8 were predicted by this tool to have an increased `therapeutic index' (TI = HC50/MIC for erythrocytes with respect to bacteria) > 80. The mutated peptides were synthesized and respectively found to have experimental TI values > 130 for S. aureus or E. coli, a considerable improvement with respect to TI < 37 for the parent compounds. Circular dichroism studies of the mutated peptides suggested this may in part be due to variations in the a-helical structure. For P. aeruginosa, which is more resistant to XT-7, the TI increased in the mutated peptide from S to >270, also due to a significant improvement in minimal inhibitory concentration. We have shown that the Mutator tool is capable of suggesting limited variations in natural anuran peptides capable of increasing peptide selectivity, by decreasing toxicity against mammalian erythrocytes, in general without compromising antibacterial activity. The tool is freely available on the Mutator Web server at http://split4.pmfst.hr/mutator/. |
| Databáze: | OpenAIRE |
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