Hybrid peptide ATCUN-sh-Buforin: Influence of the ATCUN charge and stereochemistry on antimicrobial activity

M. Daben J Libardo, Thomas J. Paul, Rajeev Prabhakar, Alfredo M. Angeles-Boza

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The emergence of antibiotic resistant strains of bacteria has resulted in the need to develop more potent antimicrobials that target microorganisms in a novel manner. Antimicrobial Peptides (AMPs) show great potential for drug development because of their broad activity and unique mechanism of action. Several AMPs contain an Amino Terminal Copper and Nickel (ATCUN) binding motif; however, its function has not yet been determined. We have previously demonstrated that the activity of a truncated version of Buforin II (sh-Buforin, RAGLQFPVGRVHRLLRK-NH<inf>2</inf>) increases by the addition of an ATCUN motif. We now focus our current studies on understanding the effect of: 1) a positively charged ATCUN sequence, and 2) l-to-d amino acid substitution on the hybrid peptides. We identified that the addition of a positively charged ATCUN motif increases the affinity of the ATCUN-AMP for DNA but does not always result in an enhanced antimicrobial activity over a neutral ATCUN motif. The all-d peptides exhibited up to a 32-fold increase in antimicrobial activity compared to the all-l peptides. The larger activity of the all-d peptides is the result of a larger DNA cleavage activity and higher stability towards proteolysis. Cytotoxicity assays determined that, at their MIC, these peptides caused less than 8% hemolysis and, at 128 μM, no toxicity to HeLa and HEK293 cell lines. These results indicate that the ATCUN-AMP hybrids are an attractive alternative for treating infectious diseases and provide key insights into the role of the ATCUN motif in naturally-occurring AMPs.

Original languageEnglish (US)
Pages (from-to)143-155
Number of pages13
JournalBiochimie
Volume113
DOIs
StatePublished - Jun 1 2015

Fingerprint

Stereochemistry
Peptides
Proteolysis
DNA Cleavage
HEK293 Cells
DNA
Amino Acid Substitution
Cytotoxicity
Hemolysis
Nickel
HeLa Cells
Microorganisms
Communicable Diseases
Toxicity
Copper
Assays
Bacteria
Substitution reactions
Cells
Anti-Bacterial Agents

Keywords

  • Antimicrobial peptide
  • ATCUN
  • Bioinorganic chemistry
  • Cytotoxicity
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hybrid peptide ATCUN-sh-Buforin : Influence of the ATCUN charge and stereochemistry on antimicrobial activity. / Libardo, M. Daben J; Paul, Thomas J.; Prabhakar, Rajeev; Angeles-Boza, Alfredo M.

In: Biochimie, Vol. 113, 01.06.2015, p. 143-155.

Research output: Contribution to journalArticle

Libardo, M. Daben J ; Paul, Thomas J. ; Prabhakar, Rajeev ; Angeles-Boza, Alfredo M. / Hybrid peptide ATCUN-sh-Buforin : Influence of the ATCUN charge and stereochemistry on antimicrobial activity. In: Biochimie. 2015 ; Vol. 113. pp. 143-155.
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