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Journal of Virology, October 2009, p. 10808-10820, Vol. 83, No. 20
0022-538X/09/$08.00+0 doi:10.1128/JVI.00977-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Peptides That Mimic the Amino-Terminal End of the Rabies Virus Phosphoprotein Have Antiviral Activity
Guillaume Castel,1
Mohamed Chtéoui,1
Grégory Caignard,2
Christophe Préhaud,3
Stéphanie Méhouas,1,4
Eléonore Réal,1,5
Corinne Jallet,1
Yves Jacob,6
Rob W. H. Ruigrok,7 and
Noël Tordo1*
Unité Postulante des Stratégies Antivirales, CNRS URA-3015, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France,1 Laboratoire de Génomique virale et Vaccination, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France,2 Unité de Neuro-Immunologie Virale, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France,3 INSERM U561, Hopital Saint Vincent de Paul, 82 Avenue Denfert Rochereau, 75014 Paris, France,4 Laboratory of Neurogenetics and Behavior, The Rockefeller University, 1230 York Avenue, New York, New York 10065,5 Unité de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France,6 Unit of Virus Host Cell Interactions, UMI 3265 UJF-EMBL-CNRS, B.P. 181 38042, Grenoble cedex 9, France7
Received 15 May 2009/ Accepted 1 August 2009
We wanted to develop a therapeutic approach against rabies disease by targeting the lyssavirus transcription/replication complex. Because this complex (nucleoprotein N-RNA template processed by the L polymerase and its cofactor, the phosphoprotein P) is similar to that of other negative-strand RNA viruses, we aimed to design broad-spectrum antiviral drugs that could be used as a complement to postexposure vaccination and immunotherapy. Recent progress in understanding the structure/function of the rabies virus P, N, and L proteins predicts that the amino-terminal end of P is an excellent target for destabilizing the replication complex because it interacts with both L (for positioning onto the N-RNA template) and N (for keeping N soluble, as needed for viral RNA encapsidation). Thus, peptides mimicking various lengths of the amino-terminal end of P have been evaluated, as follows: (i) for binding properties to the N-P-L partners by the two-hybrid method; (ii) for their capacity to inhibit the transcription/replication of a rabies virus minigenome encoding luciferase in BHK-21-T7 cells; and (iii) for their capacity to inhibit rabies virus infection of BHK-21-T7 cells and of two derivatives of the neuronal SK-N-SH cell line. Peptides P60 and P57 (the first 60 and first 57 NH2 residues of P, respectively) exhibited a rapid, strong, and long-lasting inhibitory potential on luciferase expression (>95% from 24 h to 55 h). P42 was less efficient in its inhibition level (75% for 18 to 30 h) and duration (40% after 48 h). The most promising peptides were synthesized in tandem with the Tat sequence, allowing cell penetration. Their inhibitory effects were observed on BHK-21-T7 cells infected with rabies virus and Lagos bat virus but not with vesicular stomatitis virus. In neuronal cells, a significant inhibition of both nucleocapsid inclusions and rabies virus release was observed.
* Corresponding author. Mailing address: Unité Postulante des Stratégies Antivirales, CNRS URA-3015, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France. Phone: 33 1 4061 3134. Fax: 33 1 4061 3256. E-mail: ntordo{at}pasteur.fr
Published ahead of print on 12 August 2009.
Journal of Virology, October 2009, p. 10808-10820, Vol. 83, No. 20
0022-538X/09/$08.00+0 doi:10.1128/JVI.00977-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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