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Effects of Aib residues insertion on the structural–functional properties of the frog skin-derived peptide esculentin-1a(1–21)NH2

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Abstract

Antimicrobial peptides (AMPs) play a key role in the defence mechanism of living organisms against microbial pathogens, displaying both bactericidal and immunomodulatory properties. They are considered as a promising alternative to the conventional antibiotics towards which bacteria are becoming highly resistant. Recently, a derivative of the frog skin AMP esculentin-1a, esculentin-1a(1–21)NH2 [Esc(1–21)], showed a strong and fast membranolytic activity against Gram-negative bacteria but with a lower efficacy against Gram-positive ones. Here, with the aim to increase the α-helicity of Esc(1–21) and the expected potency against Gram-positive bacteria, we designed an analog bearing three α-aminoisobutyric acid (Aib) residues at positions 1, 10, and 18 of its primary structure. We demonstrated that the incorporation of Aib residues: (1) promoted the α-helix conformation of Esc(1–21), as confirmed by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopies; (2) was sufficient to make this analog more active than the parent peptide against several Gram-positive bacterial strains without affecting its activity against Gram-negative bacteria; and (3) resulted to be devoid of toxic effect toward epithelial cells at the active antimicrobial concentrations. These results suggest that replacement of L-amino acids with Aib residues has beneficial effects on the structure and properties of the membrane-active peptide Esc(1–21), making it a better candidate for the design and development of selective drugs against Gram-positive bacteria.

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Abbreviations

CD:

Circular dichroism

DIEA:

N,N-Diisopropylethylamine

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Heat-inactivated fetal bovine serum

HATU:

1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

HBTU:

N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate

HOBt:

1-Hydroxybenzotriazole

MBHA:

4-Methylbenzhydrylamine

MH:

Mueller–Hinton

MTT:

3(4,5-Dimethylthiazol-2yl)2,5-diphenyltetrazolium bromide

NMR:

Nuclear magnetic resonance

SDS:

Sodium dodecylsulfate

TIS:

Triisopropylsilane

TFA:

Trifluoroacetic acid

TFE:

Trifluoroethanol

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Acknowledgments

This work was supported by grants from Sapienza Università di Roma and by FILAS Grant Prot. FILAS-RU-2014-1020. This article does not contain any studies with human participants or animals performed by any of the authors.

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Authors and Affiliations

  1. Institute of Biomolecular Chemistry, Padova Unit, CNR, Via Marzolo 1, 35131, Padova, Italy

    Barbara Biondi & Marco Crisma

  2. Department of Biochemical Sciences, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Via degli Apuli, 9, 00185, Rome, Italy

    Bruno Casciaro, Antonio Di Grazia, Floriana Cappiello, Vincenzo Luca & Maria Luisa Mangoni

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  1. Barbara Biondi
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  2. Bruno Casciaro
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  3. Antonio Di Grazia
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  6. Marco Crisma
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Correspondence to Maria Luisa Mangoni.

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Biondi, B., Casciaro, B., Di Grazia, A. et al. Effects of Aib residues insertion on the structural–functional properties of the frog skin-derived peptide esculentin-1a(1–21)NH2 . Amino Acids 49, 139–150 (2017). https://doi.org/10.1007/s00726-016-2341-x

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