Chang, Jinhong, Schul, Wouter, Butters, Terry D., Yip, Andy, Liu, Boping, Goh, Anne, Lakshminarayana, Suresh B., Alonzi, Dominic, Reinkensmeier, Gabriele, Pan, Xiaoben, Qu, Xiaowang, Weidner, Jessica M., Wang, Lijuan, Yu, Wenquan, Borune, Nigel, Kinch, Mark A., Rayahin, Jamie E., Moriarty, Robert, Xu, Xiaodong, and Shi, Pei-Yong
Abstract: Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II. In this report, we show that two oxygenated alkyl imino sugar derivatives, CM-9-78 and CM-10-18, are potent inhibitors of both α-glucosidases I and II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection. [ABSTRACT FROM AUTHOR]