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Design of therapeutically improved analogue of the antimicrobial peptide, indolicidin, using a glycosylation strategy

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Abstract

Indolicidin is a member of cathelicidin family which displays broad spectrum antimicrobial activity. Severe toxicity and aggregation propensity associated with indolicidin pose a huge limitation to its probable therapeutic application. We are reporting the use of glycosylation strategy to design an analogue of indolicidin and subsequently explore structural and functional effects of sugar on it. Our study led to the design of a potent antibacterial glycosylated peptide, [βGlc-T9,K7]indolicidin, which showed decreased toxicity against erythrocytes and macrophage cells and thus a higher therapeutic selectivity. The incorporation of sugar also increased the solubility of the peptide. The mode of bacterial killing, functional stability, LPS binding, and cytokine inhibitory potential of the peptide, however, seemed unaffected upon glycosylation. Absence of significant changes in structure upon glycosylation accounts for the possibly retained functions and mode of action of the peptide. Our report thus presents the designing of an indolicidin analogue with improved therapeutic potential by substituting aromatic amino acid with glycosylated amino acid as a promising strategy for the first time.

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Abbreviations

CARA:

Computer-aided resonance assignment

DCC:

N,N′-Dicyclohexyl-carbodiimide

DIPEA:

Di-isopropyl ethylamine

DMEM:

Dulbecco’s modified Eagle’s medium

DMF:

Dimethyl formamide

DMSO:

Dimethyl sulfoxide

DPC:

Dodecylphosphorylcholine

Fmoc:

9-Fluorenylmethyloxycarbonyl

HBTU:

(2-(1H-benzotraiazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HEPES:

4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid

HOBt:

1-Hydroxybenzotriazole

HPLC:

High-performance liquid chromatography

IL6:

Interleukin 6

LB:

Lysogeny broth (Luria–Bertani broth)

LBP:

Lipopolysaccharide-binding protein

LPS:

Lipopolysaccharide

MALDI-TOF:

Matrix-assisted laser desorption and ionization

MHC:

Minimum haemolytic concentration

NMP:

N-Methyl-2-pyrrolidone

RMSD:

Root-mean-square deviation

SEM:

Scanning electron microscopy

TOCSY:

Total correlation spectroscopy

TNF-α:

Tumor necrosis factor alpha

TFE:

Tri-fluoroethanol

TFA:

Trifluoroacetic acid

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Acknowledgements

We thank Department of Science and Technology (Project no.: SR/S1/OC-63/2012), India for financial support. We thank Department of Biotechnology (DBT), Government of India and ICGEB New Delhi for the NMR facility. We thank Ms. Shanta Sen for help with HRMS data. We also thank Ms. Rekha Rani for help with SEM studies and Dr. Sharad Vashisht for discussions regarding structural studies of glycopeptide.

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Authors and Affiliations

  1. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India

    Rohini Dwivedi & Kanwal J. Kaur

  2. International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India

    Priyanka Aggarwal & Neel S. Bhavesh

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  1. Rohini Dwivedi
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  2. Priyanka Aggarwal
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Contributions

KK conceived the idea of present work. KK and RD designed the experiments. RD performed the experiments. KK and RD analyzed the data and wrote the manuscript. NSB and PA performed the NMR studies.

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Correspondence to Kanwal J. Kaur.

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726_2019_2779_MOESM1_ESM.docx

NMR chemical shift values of peptides [T9,K7]indolicidin and [βGlc-T9,K7]indolicidin; PDB and BMRB accession codes of peptides; HPLC profiles of purified indolicidin, [T9,K7]indolicidin and [βGlc-T9,K7]indolicidin; HRMS spectra of indolicidin, [T9,K7]indolicidin and [βGlc-T9,K7]indolicidin; Anti-biofilm activity of peptides (DOCX 603 kb)

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Dwivedi, R., Aggarwal, P., Bhavesh, N.S. et al. Design of therapeutically improved analogue of the antimicrobial peptide, indolicidin, using a glycosylation strategy. Amino Acids 51, 1443–1460 (2019). https://doi.org/10.1007/s00726-019-02779-2

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