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Covalent binding of the natural antimicrobial peptide indolicidin to DNA abasic sites

  1. Author:
    March, C.
    Krajewski, K.
    Lee, H. F.
    Antony, S.
    Johnson, A. A.
    Amin, R.
    Roller, P.
    Kvaratskhelia, M.
    Pommier, Y.

  2. Author Address

    NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Canc Res Ctr, Frederick, MD 21702 USA. Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Hlth Sci Ctr, Columbus, OH 43210 USA.;Pommier, Y, NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA.;pommier@nih.gov
    1. Year: 2006
    2. Date: Oct
  2. Journal: Nucleic Acids Research
    1. 34
    2. 18
    3. Pages: 5157-5165
  4. Type of Article: Article
  5. ISSN: 0305-1048
  1. Abstract:

    Indolicidin is a host defense tridecapeptide that inhibits the catalytic activity of HIV-1 integrase in vitro. Here we have elucidated its mechanism of integrase inhibition. Using crosslinking and mass spectrometric footprinting approaches, we found that indolicidin interferes with formation of the catalytic integrase-DNA complex by directly binding DNA. Further characterization revealed that the peptide forms covalent links with abasic sites. Indolicidin crosslinks single- or double-stranded DNAs and various positions of the viral cDNA with comparable efficiency. Using truncated and chemically modified peptides, we show that abasic site crosslinking is independent of the PWWP motif but involves the indolicidin unique lysine residue and the N- and C- terminal NH2 groups. Because indolicidin can also inhibit topoisomerase I, we believe that multiple actions at the level of DNA might be a common property of antimicrobial peptides.

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  2. DOI: 10.1093/nar/gkl667
  3. View record in Web of Science®
  4. WOS: 000241955100023

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