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Antimicrobial Agents and Chemotherapy, April 2009, p. 1501-1508, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01457-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity against Flaviviruses{triangledown}

Jinhong Chang,1* Lijuan Wang,1 Dongling Ma,1 Xiaowang Qu,1 Haitao Guo,1 Xiaodong Xu,2,3 Peter M. Mason,4 Nigel Bourne,4 Robert Moriarty,5 Baohua Gu,1 Ju-Tao Guo,1 and Timothy M. Block1,2

Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania,1 Institute for Hepatitis and Virus Research, Hepatitis B Foundation, Doylestown, Pennsylvania,2 Pharmabridge, Inc., Doylestown, Pennsylvania 18902,3 University of Texas Medical Branch, Galveston, Texas 77555,4 University of Illinois, Chicago, Illinois 606075

Received 31 October 2008/ Returned for modification 19 December 2008/ Accepted 23 January 2009

Imino sugars, such as N-butyl-deoxynojirimycin and N-nonyl-deoxynojirimycin (NNDNJ), are glucose analogues that selectively inhibit cellular {alpha}-glucosidase I and II in the endoplasmic reticulum and exhibit antiviral activities against many types of enveloped viruses. Although these molecules have broad-spectrum antiviral activity, their development has been limited by a lack of efficacy and/or selectivity. We have previously reported that a DNJ derivative with a hydroxylated cyclohexyl side chain, called OSL-95II, has an antiviral efficacy similar to that of NNDNJ but significantly less toxicity. Building upon this observation, a family of imino sugar derivatives containing an oxygenated side chain and terminally restricted ring structures were synthesized and shown to have low cytotoxicity and superior antiviral activity against members of the Flaviviridae family, including bovine viral diarrhea virus, dengue virus (DENV), and West Nile virus. Of particular interest is that several of these novel imino sugar derivatives, such as PBDNJ0801, PBDNJ0803, and PBDNJ0804, potently inhibit DENV infection in vitro, with 90% effective concentration values at submicromolar concentrations and selectivity indices greater than 800. Therefore, these compounds represent the best in their class and may offer realistic candidates for the development of antiviral therapeutics against human DENV infections.

* Corresponding author. Mailing address: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902. Phone: (215) 589-6325. Fax: (215) 489-4920. E-mail: jinhong.chang{at}drexelmed.edu

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

Antimicrobial Agents and Chemotherapy, April 2009, p. 1501-1508, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01457-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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