This Article Full Text Full Text (PDF) 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 Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jones, T. R. Articles by O'Connell, J. Search for Related Content PubMed PubMed Citation Articles by Jones, T. R. Articles by O'Connell, J.

Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Thomas R. Jones,^1* Shi-Wu Lee,¹ Stephen V. Johann,¹ Vladimir Razinkov,² Robert J. Visalli,^1, Boris Feld,¹ Jonathan D. Bloom,³ and John O'Connell¹

Infectious Disease Section,¹ Biological Chemistry,² Chemical Sciences, Wyeth Research, Pearl River, New York 10965³

Received 20 June 2003/ Accepted 6 October 2003

A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.

Present address: Department of Biology, Indiana University—Purdue University at Fort Wayne, Fort Wayne, IN 46805.

This article has been cited by other articles:

• Fukui, Y., Shindoh, K., Yamamoto, Y., Koyano, S., Kosugi, I., Yamaguchi, T., Kurane, I., Inoue, N. (2008). Establishment of a Cell-Based Assay for Screening of Compounds Inhibiting Very Early Events in the Cytomegalovirus Replication Cycle and Characterization of a Compound Identified Using the Assay. Antimicrob. Agents Chemother. 52: 2420-2427 [Abstract] [Full Text]  
• Patrone, M., Secchi, M., Bonaparte, E., Milanesi, G., Gallina, A. (2007). Cytomegalovirus UL131-128 Products Promote gB Conformational Transition and gB-gH Interaction during Entry into Endothelial Cells. J. Virol. 81: 11479-11488 [Abstract] [Full Text]  
• Netterwald, J. R., Jones, T. R., Britt, W. J., Yang, S.-J., McCrone, I. P., Zhu, H. (2004). Postattachment Events Associated with Viral Entry Are Necessary for Induction of Interferon-Stimulated Genes by Human Cytomegalovirus. J. Virol. 78: 6688-6691 [Abstract] [Full Text]