This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Douglas, J. L.
Right arrow Articles by Cihlar, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Douglas, J. L.
Right arrow Articles by Cihlar, T.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 2005, p. 2460-2466, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2460-2466.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Small Molecules VP-14637 and JNJ-2408068 Inhibit Respiratory Syncytial Virus Fusion by Similar Mechanisms

Janet L. Douglas, Marites L. Panis, Edmund Ho, Kuei-Ying Lin, Steve H. Krawczyk, Deborah M. Grant, Ruby Cai, Swami Swaminathan, Xiaowu Chen, and Tomas Cihlar*

Gilead, 333 Lakeside Dr., Foster City, CA 94404

Received 29 August 2004/ Returned for modification 28 October 2004/ Accepted 26 December 2004

Here we present data on the mechanism of action of VP-14637 and JNJ-2408068 (formerly R-170591), two small-molecule inhibitors of respiratory syncytial virus (RSV). Both inhibitors exhibited potent antiviral activity with 50% effective concentrations (EC50s) of 1.4 and 2.1 nM, respectively. A similar inhibitory effect was observed in a RSV-mediated cell fusion assay (EC50 = 5.4 and 0.9 nM, respectively). Several drug-resistant RSV variants were selected in vitro in the presence of each compound. All selected viruses exhibited significant cross-resistance to both inhibitors and contained various single amino acid substitutions in two distinct regions of the viral F protein, the heptad repeat 2 (HR2; mutations D486N, E487D, and F488Y), and the intervening domain between HR1 and HR2 (mutation K399I and T400A). Studies using [3H]VP-14637 revealed a specific binding of the compound to RSV-infected cells that was efficiently inhibited by JNJ-2408068 (50% inhibitory concentration = 2.9 nM) but not by the HR2-derived peptide T-118. Further analysis using a transient T7 vaccinia expression system indicated that RSV F protein is sufficient for this interaction. F proteins containing either the VP-14637 or JNJ-2408068 resistance mutations exhibited greatly reduced binding of [3H]VP-14637. Molecular modeling analysis suggests that both molecules may bind into a small hydrophobic cavity in the inner core of F protein, interacting simultaneously with both the HR1 and HR2 domains. Altogether, these data indicate that VP-14637 and JNJ-2408068 interfere with RSV fusion through a mechanism involving a similar interaction with the F protein.

* Corresponding author. Mailing address: Gilead, 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 522-5637. Fax: (650) 522-5890. E-mail: tcihlar{at}gilead.com.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2460-2466, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2460-2466.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Alvarez, R., Elbashir, S., Borland, T., Toudjarska, I., Hadwiger, P., John, M., Roehl, I., Morskaya, S. S., Martinello, R., Kahn, J., Van Ranst, M., Tripp, R. A., DeVincenzo, J. P., Pandey, R., Maier, M., Nechev, L., Manoharan, M., Kotelianski, V., Meyers, R. (2009). RNA Interference-Mediated Silencing of the Respiratory Syncytial Virus Nucleocapsid Defines a Potent Antiviral Strategy. Antimicrob. Agents Chemother. 53: 3952-3962 [Abstract] [Full Text]  
  • Larson, R. A., Dai, D., Hosack, V. T., Tan, Y., Bolken, T. C., Hruby, D. E., Amberg, S. M. (2008). Identification of a Broad-Spectrum Arenavirus Entry Inhibitor. J. Virol. 82: 10768-10775 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»