This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: AAC.00289-07v1 51/7/2293    most recent Alert me when this article is cited 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 Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by White, L. K. Articles by Plemper, R. K. Search for Related Content PubMed PubMed Citation Articles by White, L. K. Articles by Plemper, R. K.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2007, p. 2293-2303, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00289-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Nonnucleoside Inhibitor of Measles Virus RNA-Dependent RNA Polymerase Complex Activity ^,

Laura K. White,^1, Jeong-Joong Yoon,¹ Jin K. Lee,¹ Aiming Sun,² Yuhong Du,³ Haian Fu,³ James P. Snyder,² and Richard K. Plemper^1*

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322,¹ Department of Chemistry, Emory University, Atlanta, Georgia 30322,² Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, Georgia 30322³

Received 27 February 2007/ Returned for modification 4 April 2007/ Accepted 20 April 2007

Paramyxoviruses comprise several major human pathogens. Although a live-attenuated vaccine protects against measles virus (MV), a member of the paramyxovirus family, the virus remains a principal cause of worldwide mortality and accounts for approximately 21 million cases and 300,000 to 400,000 deaths annually. The development of novel antivirals that allow improved case management of severe measles and silence viral outbreaks is thus highly desirable. We have previously described the development of novel MV fusion inhibitors. The potential for preexisting or emerging resistance in the field constitutes the rationale for the identification of additional MV inhibitors with a diverse target spectrum. Here, we report the development and implementation of a cell-based assay for high-throughput screening of MV antivirals, which has yielded several hit candidates. Following confirmation by secondary assays and chemical synthesis, the most potent hit was found to act as a target-specific inhibitor of MV replication with desirable drug-like properties. The compound proved highly active against multiple primary isolates of diverse MV genotypes currently circulating worldwide, showing active concentrations of 35 to 145 nM. Significantly, it does not interfere with viral entry and lacks cross-resistance with the MV fusion inhibitor class. Mechanistic characterization on a subinfection level revealed that the compound represents a first-in-class nonnucleoside inhibitor of MV RNA-dependent RNA polymerase complex activity. Singly or in combination with the fusion inhibitors, this novel compound class has high developmental potential as a potent therapeutic against MV and will likely further the mechanistic characterization of the viral polymerase complex.

Published ahead of print on 30 April 2007.

Supplemental material for this article may be found at http://aac.asm.org/.

Present address: The Scripps Research Institute, La Jolla, CA 92037.

This article has been cited by other articles:

• Yoon, J.-J., Chawla, D., Paal, T., Ndungu, M., Du, Y., Kurtkaya, S., Sun, A., Snyder, J. P., Plemper, R. K. (2008). High-Throughput Screening--Based Identification of Paramyxovirus Inhibitors. J Biomol Screen 13: 591-608 [Abstract]