viroxime and Enterovirus-Infections

Poliovirus (PV) is a small non-enveloped virus belonging to the family Picornaviridae, and is the causative agent of poliomyelitis. With established vaccines, the global eradication program for poliomyelitis is ongoing by the World Health Organization since 1988. In the eradication program, antivirals are anticipated to have some roles in the endgame and post-eradication era of PV. During our search for potent anti-PV compounds, we identified candidate compounds that are associated with a common resistance mutation in viral protein 3A similar to enviroxime (designated as enviroxime-like compounds). Recently, PIK93, an inhibitor of host phosphatidylinositol 4-kinase III beta (PI4KB), was identified as a potent anti-enterovirus compound (Hsu et al., Cell 141:799-811). We found that PIK93 is an enviroxime-like compound, and showed that T-00127-HEV1, which is a novel enviroxime-like compound identified in high-throughput screening, is a specific PI4KB inhibitor. We also showed that PI4KB is an enterovirus-specific host factor required for its viral RNA replication. Analysis of anti-enterovirus compounds would unravel novel host factors that could serve as promising antiviral targets of prophylaxis and therapy of the infection.

Topics: Antiviral Agents; Benzimidazoles; Enterovirus; Enterovirus Infections; Humans; Molecular Targeted Therapy; Oximes; Phosphotransferases (Alcohol Group Acceptor); RNA, Viral; Sulfonamides; Viral Core Proteins; Virus Replication

The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infection of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens--the rhinoviruses, the enteroviruses (including polioviruses, coxsackieviruses and echoviruses) and the hepatoviruses (including hepatitis A virus). This article will focus on the rhinoviruses and enteroviruses, agents for which substantial effort has been expended, and recent successes reported, toward the development of safe and effective antiviral therapy.

Topics: 3C Viral Proteases; Animals; Antiviral Agents; Benzimidazoles; Capsid; Cell Line; Common Cold; Cysteine Endopeptidases; Drug Resistance, Microbial; Enterovirus; Enterovirus Infections; Humans; Immunoglobulins, Intravenous; Interferons; Molecular Structure; Oximes; Picornaviridae Infections; Rhinovirus; Sulfonamides; Viral Proteins

Topics: Animals; Antiviral Agents; Benzimidazoles; Drug Resistance, Microbial; Echovirus Infections; Enterovirus; Enterovirus B, Human; Enterovirus Infections; Flavonoids; Humans; Ketones; Mice; Oximes; Picornaviridae; Picornaviridae Infections; Poliomyelitis; Poliovirus; Rats; Rhinovirus; Rhodanine; Sulfonamides

Topics: Animals; Antiviral Agents; Dibucaine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enterovirus A, Human; Enterovirus Infections; Enzyme Inhibitors; Humans; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; RNA Helicases; Structure-Activity Relationship; Viral Proteins

Antivirals against enterovirus 71 (EV71) are urgently needed. We demonstrate that the novel enteroviral protease inhibitor (PI) SG85 and capsid binder (CB) vapendavir efficiently inhibit the in vitro replication of 21 EV71 strains/isolates that are representative of the different genogroups A, B, and C. The PI rupintrivir, the CB pirodavir, and the host-targeting compound enviroxime, which were included as reference compounds, also inhibited the replication of all isolates. Remarkably, the CB compound pleconaril was devoid of any anti-EV71 activity. An in silico docking study revealed that pleconaril-unlike vapendavir and pirodavir-lacks essential binding interactions with the viral capsid. Vapendavir and SG85 (or analogues) should be further explored for the treatment of EV71 infections. The data presented here may serve as a reference when developing yet-novel inhibitors.

Topics: Antiviral Agents; Benzimidazoles; Capsid; Capsid Proteins; Drug Resistance, Viral; Enterovirus A, Human; Enterovirus Infections; Isoxazoles; Molecular Docking Simulation; Oximes; Phenylalanine; Piperidines; Protease Inhibitors; Protein Binding; Pyridazines; Pyrrolidinones; Sulfonamides; Valine; Virus Replication

To further explore the anti-enteroviral activity of 9-aryl-6-chloropurines, three different series of compounds with a dialkylamino, (alkyl)amido, or oxazolidinone substituent at the aryl ring have been synthesized, in most cases with the aid of microwave-assisted synthesis. The resulting compounds efficiently inhibit Coxsackie virus type B3 (CVB3) replication with EC(50) values varying from 3 to 15 μM, and with no significant toxicity in Vero cells. The most potent compounds also selectively inhibit the replication of other enteroviruses including Coxsackie virus B4 and Echo virus 11. The cross-resistance studies performed with different 9-aryl-6-chloropurines indicate that they all belong to the same pharmacological family and differ from other CVB3 drugs such as enviroxime.

Topics: Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Enterovirus B, Human; Enterovirus Infections; Halogenation; Humans; Microbial Sensitivity Tests; Microwaves; Models, Molecular; Oxazolidinones; Purines; Vero Cells