Novel imino sugar derivatives demonstrate potent antiviral activity against flaviviruses.
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.
Chang
Jinhong
J
Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Doylestown, Pennsylvania 18902, USA. jinhong.chang@drexelmed.edu
Wang
Lijuan
L
Ma
Dongling
D
Qu
Xiaowang
X
Guo
Haitao
H
Xu
Xiaodong
X
Mason
Peter M
PM
Bourne
Nigel
N
Moriarty
Robert
R
Gu
Baohua
B
Guo
Ju-Tao
JT
Block
Timothy M
TM
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D005416:Flavivirus / Q000187:drug effects*; D065089:Glycoside Hydrolase Inhibitors; D050111:Imino Sugars / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D065089:Glycoside Hydrolase Inhibitors; D050111:Imino Sugars; C112150:N-nonyl-1-deoxynojirimycin; D017485:1-Deoxynojirimycin