QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.006254v1 67/3/877    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Philips, B. J. Articles by Beerman, T. A. Search for Related Content PubMed PubMed Citation Articles by Philips, B. J. Articles by Beerman, T. A.

ORIGINAL ARTICLE

DNA Damage Effects of a Polyamide-CBI Conjugate in SV40 Virions

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York (B.J.P., T.A.B.); the Scripps Research Institute, La Jolla, California (A.Y.C); and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California (A.Y.C., P.B.D.)

Abstract

Polyamides are a class of synthetic molecules that exhibit high-affinity, sequence-specific reversible binding in the DNA minor groove but are incapable of inducing DNA damage. In cell-free systems, polyamides have been shown to regulate gene expression by activation, repression, and antirepression. However, effectiveness in cell culture has met with limited success and seems to be cell-dependent. By combining a polyamide with a moiety of a DNA-alkylating agent of the cyclopropylpyrroloindole (CPI) family, a conjugate molecule [polyamide 1-CBI (1-(chloromethyl)-5-hydroxyl-1,2-dihydro-3H-benz[e]indole) conjugate] capable of sequence-specific DNA alkylation was shown to exhibit cellular activity (i.e., cell-growth inhibition and cell-cycle arrest) in mammalian cells. These effects, however, occur at concentrations several orders of magnitude higher than those of its parent CPI agent adozelesin. In addition, 1-CBI is able to interact sequence-specifically with viral DNA and inhibit SV40 DNA replication in infected BSC-1 (African green monkey kidney epithelial) cells, albeit at a greatly reduced ability compared with its CPI parent. On the basis of results from previous studies, we tested whether pretreatment of virus with 1-CBI, compared with direct treatment of infected cells, would enhance its cellular activity. Therefore, using SV40 virions as a model system, we examined the ability of this conjugate molecule to penetrate SV40 virions and damage viral DNA. Our results demonstrate that 1-CBI is able to damage encapsidated SV40 DNA. Both DNA replication and virus production are effectively inhibited in a concentration-dependent manner after infection of BSC-1 cells with 1-CBI–pretreated virions. It is surprising that, unlike in mammalian cells, the relative activity of 1-CBI in SV40 virions is comparable with that of the highly cytotoxic CPI agent adozelesin. Because 1-CBI is able to efficiently penetrate virions and damage DNA, these findings may provide the framework for the development of polyamide-based antiviral agents with enhanced sequence-preference capabilities.

Address correspondence to: Dr. Terry A. Beerman, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: terry.beerman{at}roswellpark.edu

This article has been cited by other articles:

				P. Simon, F. Cannata, L. Perrouault, L. Halby, J.-P. Concordet, A. Boutorine, V. Ryabinin, A. Sinyakov, and C. Giovannangeli Sequence-specific DNA cleavage mediated by bipyridine polyamide conjugates Nucleic Acids Res., June 1, 2008; 36(11): 3531 - 3538. [Abstract] [Full Text] [PDF]