When skeletons of Win compounds were used as templates, computer-assisted drug design led to the identification of a novel series of imidazolidinone derivatives with significant antiviral activity against enterovirus 71 (EV 71), the infection of which had resulted in about 80 fatalities during the 1998 epidemic outbreak in Taiwan. In addition to inhibiting all the genotypes (A, B, and C) of EV 71 in the submicromolar to low micromolar range, compounds 1 and 8 were extensively evaluated against a variety of viruses, showing potent activity against coxsackievirus A9 (IC(50) = 0.47-0.55 microM) and coxsackievirus A24 (IC(50) = 0.47-0.55 microM) as well as moderate activity against enterovirus 68 (IC(50) = 2.13 microM) and echovirus 9 (IC(50) = 2.6 microM). Our SAR studies revealed that imidazolidinone analogues with an aryl substituent at the para position of the phenoxyl ring, such as compounds 20, 21, 27, 57, 58, and 61, in general exhibited the highest activity against EV 71. Among them, compound 20 and its corresponding hydrochloride salt 57, in terms of potency and selectivity index, appear to be the most promising candidates in this series for further development of anti-EV-71 agents. Preliminary results of the study on the mode of action by a time-course experiment suggest that test compounds 1 and 8 can effectively inhibit the virus replication at the early stages, referring to virus attachment or uncoating. This indicates that the surface protein may be the target for this type of compounds.

Abstract-Internet-of-Things (IoTs) envisions to integrate, coordinate, communicate, and collaborate real-world objects in order to perform daily tasks in a more intelligent and efficient manner. To comprehend this vision, this paper studies the design of a large scale IoT system for smart grid application, which constitutes a large number of home users and has the requirement of fast response time. In particular, we focus on the messaging protocol of a universal IoT home gateway, where our cloud enabled system consists of a backend server, unified home gateway (UHG) at the end users, and user interface for mobile devices. We discuss the features of such IoT system to support a large scale deployment with a UHG and real-time residential smart grid applications. Based on the requirements, we design an IoT system using the XMPP protocol, and implemented in a testbed for energy management applications. To show the effectiveness of the designed testbed, we present some results using the proposed IoT architecture.

Enterovirus 71 is one of the most important pathogens in the family of Picornaviridae that can cause severe complications in the postpoliovirus era, such as encephalitis, pulmonary edema, and even death. Pyridyl imidazolidinone is a novel class of potent and selective human enterovirus 71 inhibitor. Pyridyl imidazolidinone was identified by using computer-assisted drug design. This virologic investigation demonstrates that BPR0Z-194, one of the pyridyl imidazolidinones, targets enterovirus 71 capsid protein VP1. Time course experiments revealed that BPR0Z-194 effectively inhibited virus replication in the early stages, implying that the compound can inhibit viral adsorption and/or viral RNA uncoating. BPR0Z-194 was used to select and characterize the drug-resistant viruses. Sequence analysis of the VP1 region showed that the resistant variants differed consistently by seven amino acids in VP1 region from their parental drug-sensitive strains. Sitedirected mutagenesis of enterovirus 71 infectious cDNA revealed that a single amino acid alteration at the position 192 of VP1 can confer resistance to the inhibitory effects of BPR0Z-194.Enterovirus 71 (EV71) was first isolated in 1969 in California (J. Blomberg, E. Lycke, K. Ahlfors, T. Johnsson, S. Wolontis, and G. von Zeipel, Letter, Lancet i:112). Two adults and 18 children were infected in that outbreak and one 5-year-old child died. Thereafter, mortalities caused by EV71 were reported in Bulgaria (6), Hungary (23), and Malaysia. In 1998, an EV71 epidemic occurred in Taiwan, with the virus infecting over 120,000 people and killing 78 children (1,5,13,14). The central nervous system is the most vulnerable target of EV71 infection. After the central nervous system is virus infected, a patient can die very quickly from severe complications, such as encephalitis (19) and pulmonary edema (2, 16).EV71, like other viruses in the family of Picornaviridae, is a small, nonenveloped, spherical particle with a diameter of ϳ30 nm. The virus has a single-stranded positive-sense RNA enclosed by the capsid proteins VP1, VP2, VP3, and VP4. The capsid contains 60 structural proteins symmetrically arranged into an icosahedral lattice (15,31,32). In addition to protecting the viral RNA from nuclease cleavage, the capsid recognizes the receptors on the surface of the specific host cells (3, 9, 18) and displays antigenicity (20,38). The surface of the virion has a prominent star-shaped plateau at the fivefold axis of symmetry, surrounded by a deep depression ("canyon"). The canyon has been shown to serve as a receptor-binding site in poliovirus and rhinovirus (29,30).Pleconaril, one of the WIN compounds with capsid-binding capability targeting VP1, is a novel agent for treating picornavirus infections. Pleconaril has passed the last stage of clinical trials (4, 26) and has shown excellent antiviral effects for most of the enteroviruses and rhinoviruses (27,28,33,34). However, pleconaril did not neutralize the cytopathic effect (CPE) induced by EV71 (37). Therefore, a series of imidazol...

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