Dolle, A and Nagati, VB and Hunashal, Y and Krishnamurthy, K and Pasupulati, AK and Raghothama, S and Gowd, KH (2019) Disulfide engineering on temporin-SHf: Stabilizing the bioactive conformation of an ultra-short antimicrobial peptide. In: Chemical Biology and Drug Design, 94 (3). pp. 1634-1646.
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Abstract
In Silico searching for short antimicrobial peptides has revealed temporin-SHf as the short (8AA), hydrophobic, broad spectrum, and natural antimicrobial peptide. Important drawback associated with temporin-SHf is the susceptibility of its bioactive conformation for denaturation and proteolytic degradation. In the current report, disulfide engineering strategy has been adopted to improve the stability of bioactive conformation of temporin-SHf. The functionally non-critical Leu4 and Ile7 residues at i and i + 3 position of helical conformation of temporin-SHf were mutated with cysteine disulfide. Designed [L4C, I7C]temporin-SHf was synthesized, characterized using NMR spectroscopy, and accessed for antimicrobial activity. [L4C, I7C]Temporin-SHf adopts helical conformation from Phe3 to Phe8 in the absence of membrane-mimetic environment and retains broad spectrum antimicrobial activity. The reduction potential of cysteine disulfide of [L4C, I7C]temporin-SHf is −289 mV. Trypsin-induced digestion and serum-induced digestion have confirmed the advantage of cysteine disulfide in imparting proteolytic stability to temporin-SHf. Disulfide-stabilized temporin-SHf may serve as a good model for the rational design of temporin-SHf based antibiotics for treatment of infectious diseases.
| Item Type: | Journal Article |
|---|---|
| Publication: | Chemical Biology and Drug Design |
| Publisher: | Blackwell Publishing Ltd |
| Additional Information: | The copyright for this article belongs to Blackwell Publishing Ltd |
| Keywords: | ampicillin; cysteine; disulfide; dithiothreitol; glutathione; glutathione disulfide; leucine; peptidomimetic agent; polypeptide antibiotic agent; synthetic peptide; temporin shf; trypsin; unclassified drug; antiinfective agent; antimicrobial cationic peptide; peptide; protein binding; temporin, Article; Bacillus subtilis; controlled study; disk diffusion; disulfide bond; drug conformation; drug stability; electrospray mass spectrometry; Escherichia coli; heteronuclear single quantum coherence; hydrophobicity; minimum inhibitory concentration; nonhuman; nuclear magnetic resonance spectroscopy; peptide synthesis; priority journal; protein degradation; proton nuclear magnetic resonance; Pseudomonas aeruginosa; reduction (chemistry); reversed phase high performance liquid chromatography; solid phase synthesis; Staphylococcus aureus; zone of inhibition; amino acid sequence; chemical phenomena; chemistry; conformation; drug design; microbial sensitivity test; molecular model; pH; protein denaturation, Amino Acid Sequence; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Disulfides; Drug Design; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Peptides; Protein Binding; Protein Denaturation; Proteolysis |
| Department/Centre: | Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility) |
| Date Deposited: | 07 Jan 2023 05:04 |
| Last Modified: | 07 Jan 2023 05:04 |
| URI: | https://eprints.iisc.ac.in/id/eprint/78846 |
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