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DNA damage effects of a polyamide-CBI conjugate in SV40 virions

Philips, Brian J. and Chang, Aileen Y. and Dervan, Peter B. and Beerman, Terry A. (2005) DNA damage effects of a polyamide-CBI conjugate in SV40 virions. Molecular Pharmacology, 67 (3). pp. 877-882. ISSN 0026-895X. doi:10.1124/mol.104.006254.

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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.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2005 The American Society for Pharmacology and Experimental Therapeutics. Received August 16, 2004; accepted November 10, 2004. Published online before print December 2, 2004. We thank Dr. Christine M. White and Loretta Gawron for technical assistance. This study was supported by National Institutes of Health grants CA80939 and CA16056 (to T.A.B.) and GM27681 (to P.B.D.). This work was previously presented at the DNA Replication and Repair Symposium, Roswell Park Cancer Institute, Buffalo, NY, June 2003.
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Record Number:CaltechAUTHORS:20160509-110456160
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Official Citation:Brian J. Philips, Aileen Y. Chang, Peter B. Dervan, and Terry A. Beerman DNA Damage Effects of a Polyamide-CBI Conjugate in SV40 Virions Mol Pharmacol March 2005 67:877-882; published ahead of print December 2, 2004, doi:10.1124/mol.104.006254
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66759
Deposited By: Victoria Brennan
Deposited On:17 May 2016 22:28
Last Modified:11 Nov 2021 00:02

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