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Nucleic Acids Research Advance Access originally published online on September 22, 2006
Nucleic Acids Research 2006 34(18):5157-5165; doi:10.1093/nar/gkl667
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Nucleic Acids Research, 2006, Vol. 34, No. 18 5157-5165
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

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

Christophe Marchand, Krzysztof Krajewski1, Hsiu-Fang Lee2, Smitha Antony, Allison A. Johnson, Ronak Amin, Peter Roller1, Mamuka Kvaratskhelia2 and Yves Pommier*

Laboratory of Molecular Pharmacology, Center for Cancer Research Building 37, Room 5068 National Cancer Institute, National Institutes of Health Bethesda, MD 20892-4255, USA 1 Laboratory of Medicinal Chemistry, Center for Cancer Research National Cancer Institute, Frederick, MD 21702, USA 2 College of Pharmacy, Center for Retrovirus Research and Comprehensive Cancer Center The Ohio State University Health Sciences Center, Columbus, OH 43210, USA

*To whom correspondence should be addressed. Tel: +1 301 496 5944; Fax: +1 301 402 0752; Email: pommier{at}nih.gov

Received July 26, 2006. Revised August 29, 2006. Accepted August 29, 2006.

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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