This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
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 Google Scholar
Google Scholar
Right arrow Articles by Wang, Q.-Y.
Right arrow Articles by Vasudevan, S. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wang, Q.-Y.
Right arrow Articles by Vasudevan, S. G.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2009, p. 1823-1831, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01148-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Small-Molecule Dengue Virus Entry Inhibitor{triangledown} ,{dagger}

Qing-Yin Wang,1*,{ddagger} Sejal J. Patel,1,{ddagger},§ Eric Vangrevelinghe,2 Hao Ying Xu,1 Ranga Rao,1 Deana Jaber,1 Wouter Schul,1 Feng Gu,1 Olivier Heudi,1,§ Ngai Ling Ma,1 Mee Kian Poh,1 Wai Yee Phong,1 Thomas H. Keller,1 Edgar Jacoby,2 and Subhash G. Vasudevan1,¶

Novartis Institute for Tropical Diseases, Singapore 138670, Singapore,1 Novartis Institutes for BioMedical Research, Basel CH4002, Switzerland2

Received 27 August 2008/ Returned for modification 24 October 2008/ Accepted 30 January 2009

The incidence of dengue fever epidemics has increased dramatically over the last few decades. However, no vaccine or antiviral therapies are available. Therefore, the need for safe and effective antiviral drugs has become imperative. The entry of dengue virus into a host cell is mediated by its major envelope (E) protein. The crystal structure of the E protein reveals a hydrophobic pocket that is presumably important for low-pH-mediated membrane fusion. High-throughput docking with this hydrophobic pocket was performed, and hits were evaluated in cell-based assays. Compound 6 was identified as one of the inhibitors and had an average 50% effective concentration of 119 nM against dengue virus serotype 2 in a human cell line. Mechanism-of-action studies demonstrated that compound 6 acts at an early stage during dengue virus infection. It arrests dengue virus in vesicles that colocalize with endocytosed dextran and inhibits NS3 expression. The inhibitors described in this report can serve as molecular probes for the study of the entry of flavivirus into host cells.

* Corresponding author. Mailing address: Novartis Institute for Tropical Diseases, 10 Biopolis Rd., Chromos Building, Singapore 138670, Singapore. Phone: (65) 6722-2986. Fax: (65) 6722-2916. E-mail: qing_yin.wang{at}novartis.com.

{triangledown} Published ahead of print on 17 February 2009.

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

{ddagger} These authors contributed equally.

§ Present address: Novartis Institutes for BioMedical Research, Basel, Switzerland.

Present address: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 2 Jalan Bukit Merah, Singapore 169547, Singapore.

Antimicrobial Agents and Chemotherapy, May 2009, p. 1823-1831, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01148-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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