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Journal of Virology, April 2002, p. 3881-3891, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3881-3891.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production

Neerja Kaushik,1,2 Amartya Basu,1,2 Paul Palumbo,3 Rene L. Myers,4 and Virendra N. Pandey1,2*

Center for the Study of Emerging and Re-Emerging Pathogens,1 Department of Biochemistry and Molecular Biology,2 Division of Allergy, Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103,3 Applied Biosystems, Framingham, Massachusetts 017014

Received 17 September 2001/ Accepted 11 January 2002

The emergence of drug-resistant variants has posed a significant setback against effective antiviral treatment for human immunodeficiency virus (HIV) infections. The choice of a nonmutable region of the viral genome such as the conserved transactivation response element (TAR element) in the 5' long terminal repeat (LTR) may potentially be an effective target for drug development. We have earlier demonstrated that a polyamide nucleotide analog (PNA) targeted to the TAR hairpin element, when transfected into cells, can effectively inhibit Tat-mediated transactivation of HIV type 1 (HIV-1) LTR (T. Mayhood et al., Biochemistry 39:11532-11539, 2000). Here we show that this anti-TAR PNA (PNATAR), upon conjugation with a membrane-permeating peptide vector (transportan) retained its affinity for TAR in vitro similar to the unconjugated analog. The conjugate was efficiently internalized into the cells when added to the culture medium. Examination of the functional efficacy of the PNATAR-transportan conjugate in cell culture using luciferase reporter gene constructs resulted in a significant inhibition of Tat-mediated transactivation of HIV-1 LTR. Furthermore, PNATAR-transportan conjugate substantially inhibited HIV-1 production in chronically HIV-1-infected H9 cells. The mechanism of this inhibition appeared to be regulated at the level of transcription. These results demonstrate the efficacy of PNATAR-transportan as a potential anti-HIV agent.

* Corresponding author. Mailing address: Center for the Study of Emerging and Re-Emerging Pathogens, Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103. Phone: (973) 972-0660. Fax: (973) 972-5594. E-mail: pandey{at}umdnj.edu.

Journal of Virology, April 2002, p. 3881-3891, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3881-3891.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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