Dataset Information

Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei.

ABSTRACT: The modern world has no available drugs for the treatment of enteroviruses (EV), which affect millions of people worldwide each year. The EV71 is a major causative disease for hand, foot, and mouth disease; sometimes it is associated with severe central nervous system diseases. Treatment for enteroviral infection is mainly supportive; treatment for aseptic meningitis caused by enteroviruses is also generally symptomatic. Upon the urgent request of new anti-enterovirus drugs, a series of hinged aromatic compounds with polynulei were synthesized through two different chemical pathways. Among these morpholine-furan/thiophene/pyrrole-benzene-pyrazole conjugates, three new agents exhibited inhibitory activity with EC50 = 2.29-6.16 ?M toward EV71 strain BrCr in RD cells. Their selectivity index values were reached as high as 33.4. Their structure-activity relationship was deduced that a thiophene derivative with morpholine and trifluorobenzene rings showed the greatest antiviral activity, with EC50 = 2.29 ?M.

SUBMITTER: Hwu JR

PROVIDER: S-EPMC7503712 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei.

Hwu Jih Ru JR Panja Avijit A Jayakumar Srinivasan S Tsay Shwu-Chen SC Tan Kui-Thong KT Huang Wen-Chieh WC Hu Yu-Chen YC Leyssen Pieter P Neyts Johan J

Molecules (Basel, Switzerland) 20200822 17

The modern world has no available drugs for the treatment of enteroviruses (EV), which affect millions of people worldwide each year. The EV71 is a major causative disease for hand, foot, and mouth disease; sometimes it is associated with severe central nervous system diseases. Treatment for enteroviral infection is mainly supportive; treatment for aseptic meningitis caused by enteroviruses is also generally symptomatic. Upon the urgent request of new anti-enterovirus drugs, a series of hinged a ...[more]

PMID: 32842645

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Project description:Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia. There is no clinically approved vaccine or antiviral therapy for EV71 infection. NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA synthesis. Here we report that NITD008 has potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 at a 50% effective concentration of 0.67 μM and a 50% cytotoxic concentration of 119.97 μM. When administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads in various organs and completely prevented clinical symptoms and death. To study the antiviral mechanism and drug resistance, we selected escape mutant viruses by culturing EV71 with increasing concentrations of NITD008. Resistance mutations were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation alone could lead to resistance to NITD008. A combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between the 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment. Importance: Human enterovirus 71 (EV71) has emerged as a major cause of viral encephalitis in children worldwide, especially in the Asia-Pacific region. Vaccines and antivirals are urgently needed to prevent and treat EV71 infections. In this study, we report the in vitro and in vivo efficacy of NITD008 (an adenosine analog) as an inhibitor of EV71. The efficacy results validated the potential of nucleoside analogs as antiviral drugs for EV71 infections. Mechanistically, we showed that mutations in the viral 3A and 3D polymerases alone or in combination could confer resistance to NITD008. The resistance results suggest an intrinsic interaction between viral proteins 3A and 3D during replication, as well as the importance of combination therapy for the treatment of EV71 infections.

Dataset Information

Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei.

Publications

Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei.

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