oxadiazoles and Enterovirus-Infections

Nonpolio enteroviruses and parechoviruses are frequent causes of neonatal infection. Clinical manifestations of infection range from asymptomatic infection to mild infection without sequelae to septic shock with muiltiorgan failure. Neonates with clinically apparent infection typically have mothers and/or other contacts with recent symptoms consistent with a viral illness. Severe neonatal infection with nonpolio enterovirus or parechovirus cannot be differentiated clinically from serious bacterial infection. The preferred method for diagnosing neonatal nonpolio enterovirus or parechovirus infection is PCR as it is rapid, sensitive, specific, and commercially available for the detection of virus from various clinical specimens. Investigational agents such as the capsid inhibitors pleconaril and pocapavir show promise for treatment of neonatal enterovirus infections, and other investigational agents are being developed. This review focuses on the epidemiology, diagnosis, and treatment of neonatal nonpolio enterovirus and parechovirus infections.

Topics: Antiviral Agents; Cross Infection; Enterovirus; Enterovirus Infections; Female; Fomites; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Oxadiazoles; Oxazoles; Parechovirus; Phenyl Ethers; Picornaviridae Infections; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Infectious

Viral infections in the fetus or newborn often involve the central nervous system (CNS) and can lead to significant morbidity and mortality. Substantial progress has been made in identifying interventions decreasing adverse neurodevelopmental outcomes in this population. This review highlights progress in treatment of important viruses affecting the CNS in these susceptible hosts, focusing on herpes simplex virus (HSV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and enteroviruses. The observation that high-dose acyclovir improves mortality in neonatal HSV disease culminated decades of antiviral research for this disease. More recently, prolonged oral acyclovir was found to improve neurologic morbidity after neonatal HSV encephalitis. Ganciclovir, and more recently its oral prodrug valganciclovir, is effective in improving hearing and neurodevelopment after congenital CMV infection. Increasing evidence suggests early control of perinatal HIV infection has implications for neurocognitive functioning into school age. Lastly, the antiviral pleconaril has been studied for nearly two decades for treating severe enteroviral infections, with newer data supporting a role for this drug in neonates. Identifying common mechanisms for pathogenesis of viral CNS disease during this critical period of brain development is an important research goal, highlighted by the recent emergence of Zika virus as a potential cause of fetal neurodevelopmental abnormalities.

Topics: Acyclovir; Antiviral Agents; Brain; Cognition; Cognition Disorders; Encephalitis, Herpes Simplex; Enterovirus Infections; Female; Ganciclovir; HIV Infections; Humans; Infant, Newborn; Nervous System Diseases; Oxadiazoles; Oxazoles; Pregnancy; Valganciclovir; Virus Diseases

Specific antiviral therapy is currently not available for enterovirus (EV) infections. Poliomyelitis, EV 71 neurologic disease, and neonatal EV disease are three manifestations of EV infections that exemplify the importance of developing antivirals for EV infections. Despite tremendous strides in the effort to eradicate polio through vaccination, challenges remain, including the potential for transmission of neurovirulent vaccine-derived polioviruses which have genetically reverted from live-attenuated, oral poliovirus vaccine virus. EV 71 emerged in the late 1990 s in eastern Asia as a neurovirulent virus that causes large outbreaks of hand-foot-mouth disease, herpangina, and fever, and, in some children, meningitis, acute flaccid paralysis, and brainstem encephalitis complicated by pulmonary edema and cardiopulmonary collapse. EV infections in neonates can cause severe disease characterized by meningoencephalitis, myocarditis, pneumonitis, and/or hepatitis and coagulopathy. Prototypic agents for specific therapy of EV infections that act upon numerous potential viral targets exist. Three candidate compounds are currently in development: pleconaril (active against many EVs), V-073 (anti-poliovirus), and BTA-798 (active against many rhinoviruses and EVs). The three conditions described illustrate why development of antiviral medications for EV infections is a medically important need.

Topics: Antiviral Agents; Drug Discovery; Enterovirus Infections; Global Health; Humans; Oxadiazoles; Oxazoles

Although poliomyelitis has been mostly eradicated worldwide, large outbreaks of the related enterovirus 71 have been seen in Asia-Pacific countries in the past 10 years. This virus mostly affects children, manifesting as hand, foot, and mouth disease, aseptic meningitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, and other severe systemic disorders, including especially pulmonary oedema and cardiorespiratory collapse. Clinical predictors of severe disease include high temperature and lethargy, and lumbar puncture might reveal pleocytosis. Many diagnostic tests are available, but PCR of throat swabs and vesicle fluid, if available, is among the most efficient. Features of inflammation, particularly in the anterior horns of the spinal cord, the dorsal pons, and the medulla can be clearly seen on MRI. No established antiviral treatment is available. Intravenous immunoglobulin seems to be beneficial in severe disease, perhaps through non-specific anti-inflammatory mechanisms, but has not been tested in any formal trials. Milrinone might be helpful in patients with cardiac dysfunction.

Topics: Disease Management; Enterovirus A, Human; Enterovirus Infections; Humans; Oxadiazoles; Oxazoles

Topics: Antiviral Agents; Enterovirus Infections; Humans; Immunocompromised Host; Oxadiazoles; Oxazoles; Poliovirus

The nonpoliovirus enteroviruses commonly infect newborns, with consequences ranging from asymptomatic infection and benign illness, to severe, life-threatening disease. Frequently occurring symptoms include fever, irritability, lethargy, anorexia, and rash. Although most illnesses are mild, severe disease develops in a subset of newborns infected in the first 2 weeks of life. Severe disease may consist of sepsis, meningoencephalitis, myocarditis, pneumonia, hepatitis, and/or coagulopathy. Substantial mortality rates have been reported, and long-term sequelae may occur among survivors. Risk factors and clinical features associated with severe disease include absence of neutralizing antibody to the infecting serotype, maternal illness prior to or at delivery, prematurity, illness onset within the first few days of life, multiorgan disease, severe hepatitis, positive serum viral culture, and specific infecting serotype (e.g. group B coxsackieviruses and echovirus 11). Whereas the mainstay of diagnosis has traditionally been viral isolation in tissue culture, the polymerase chain reaction has been demonstrated to be more sensitive than culture, highly specific, and rapid. Immunoglobulin has been used as a therapeutic agent for neonates with enterovirus disease; however, clinical efficacy has not been proven. Specific antiviral therapy for enteroviruses is in development. Pleconaril is an investigational agent that inhibits viral attachment to host cell receptors and uncoating of viral nucleic acid. It has broad and potent anti-enterovirus activity, excellent oral bioavailability, and is well tolerated. Some clinical trials have demonstrated benefit in children and adults with enterovirus meningitis, and in adults with upper respiratory tract infections caused by picornaviruses (rhinoviruses or enteroviruses). Data summarizing compassionate use for severe enterovirus diseases (including neonatal sepsis) also suggest possible benefit. Limited pharmacokinetic data are available in infants and neonates. A multicenter, placebo-controlled, randomized trial of pleconaril in neonates with severe hepatitis, coagulopathy, and/or myocarditis is currently being conducted.

Topics: Adult; Antiviral Agents; Child; Enterovirus Infections; Humans; Infant, Newborn; Oxadiazoles; Oxazoles; Randomized Controlled Trials as Topic; Viral Vaccines

Enteroviruses cause infections that present in diverse ways and affect people of all ages. Infections peak during summer and fall epidemics and cause 10 to 15 million symptomatic infections annually in the United States. The 70 enteroviral serotypes cause illness that ranges from nonspecific fevers and rashes to life-threatening myocarditis or central nervous system disease. These common infections create a significant burden on our society and healthcare system. New developments in rapid diagnosis of enterovirus infections using polymerase chain reaction (PCR) positively affect patient management and have the potential to reduce the healthcare impact of enterovirus infection. The future holds promise for effective antiviral drugs that can treat enterovirus infections and decrease their significant morbidity and mortality.

Topics: Adult; Antiviral Agents; Child; Clinical Trials as Topic; Enterovirus Infections; Humans; Meningitis, Viral; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Virus Replication

Enterovirus infections are common in both children and adults and range from benign short-lived febrile illnesses to life-threatening infections. Recent developments in nucleic acid amplification techniques now allow the rapid and sensitive diagnosis of enterovirus infections, which in turn can lead to improvements in patient management that shorten hospitalizations and reduce costs. New antiviral drugs have been developed that inhibit enterovirus replication, and early clinical trials of these compounds suggest that effective therapy for enterovirus infections is now possible.

Topics: Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Enterovirus Infections; Female; Humans; Infant; Infant, Newborn; Meningitis, Viral; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Infectious; Sepsis

Topics: Antiviral Agents; Cost-Benefit Analysis; Disease Outbreaks; Enterovirus Infections; Humans; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Romania; Scotland

Topics: Adult; Antiviral Agents; Enterovirus Infections; Humans; Immunization, Passive; Infant, Newborn; Oxadiazoles; Oxazoles; Randomized Controlled Trials as Topic

Topics: Antiviral Agents; Child; Cost of Illness; Enterovirus; Enterovirus Infections; Humans; Meningitis, Viral; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Serologic Tests

Topics: Anti-Bacterial Agents; Antiviral Agents; Bacteria; Bacterial Infections; Enterovirus; Enterovirus Infections; Humans; Oxadiazoles; Oxazoles; Virus Diseases; Viruses

Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available.. Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed.. Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events.. Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.

Topics: Antiviral Agents; Double-Blind Method; Enterovirus; Enterovirus Infections; Female; Humans; Infant; Infant, Newborn; Male; Neonatal Sepsis; Oropharynx; Oxadiazoles; Oxazoles; Rectum

Topics: Antiviral Agents; Double-Blind Method; Enterovirus Infections; Female; Humans; Infant, Newborn; Male; Neonatal Sepsis; Oxadiazoles; Oxazoles; Placebo Effect; Reproducibility of Results; Time Factors; Treatment Outcome

Enteroviral meningitis causes appreciable morbidity in adults, including hospitalization, decreased activity, and headache. Limited data define the natural history of disease. No antiviral therapeutic agent has demonstrated improved outcome in controlled clinical trials. Pleconaril, an inhibitor of enterovirus replication, was tested in two placebo-controlled clinical trials. Of 607 randomized patients in a multicenter, double-blind placebo-controlled study of pleconaril (200 mg three times daily versus an identical-appearing placebo), 240 patients were confirmed to have enterovirus infection. The time to headache resolution was evaluated by using Kaplan-Meier survival methodology. A Cox regression model evaluated multivariate factors associated with disease resolution. Resolution of headache in patients with concomitant moderate to severe nausea at baseline occurred at a median of 9.5 days in the absence of therapy and was reduced to 7.0 days for pleconaril recipients (P = 0.009). For a headache score of > 5 alone, treated patients resolved headache significantly more rapidly (P = 0.005). Males resolved headache 50% faster than females. Regardless of randomization group, patients with a baseline headache score of 5 or greater resolved headache 50% more slowly than patients with a baseline headache score of 4. No differences in either clinical or laboratory adverse events were noted. Over 50% of untreated patients had a persistent headache that was greater than 1 week in duration. Pleconaril shortened the course of illness compared to placebo recipients, especially in the early disease course. However, the benefit was achieved only modestly in a subgroup analysis of patients with more severe disease after adjusting for confounding variables.

Topics: Adult; Antiviral Agents; Double-Blind Method; Enterovirus Infections; Female; Headache; Humans; Male; Meningitis, Viral; Multivariate Analysis; Oxadiazoles; Oxazoles; Treatment Outcome

Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis.. Infants < or =12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations.. Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (< or =50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally > or =50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups.. The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.

Topics: Administration, Oral; Biological Availability; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enterovirus Infections; Female; Follow-Up Studies; Humans; Infant; Male; Meningitis, Viral; Oxadiazoles; Oxazoles; Probability; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome

Enteroviruses usually cause self-limited disease that, although associated with high morbidity, is rarely fatal. In certain patient populations, however, the enteroviruses may cause potentially life-threatening infections. Pleconaril is a novel compound that integrates into the capsid of picornaviruses, including enteroviruses and rhinoviruses, preventing the virus from attaching to cellular receptors and uncoating to release RNA into the cell. Pleconaril was used on a compassionate-release basis to treat patients with potentially life-threatening enterovirus infections, and for 38 of these patients sufficient follow-up data were available for determining responses to therapy. Response was evaluated in 4 categories: clinical, virological, laboratory, and radiological. Most patients (28 [78%] of 36), including 12 of 16 with chronic enterovirus meningoencephalitis, were judged to have a clinical response temporally associated with pleconaril therapy. Similarly, nearly all patients whose virological responses (12 [92%] of 13), laboratory responses (14 [88%] of 16), and radiological responses (3 [60%] of 5) could be evaluated were judged to have responded favorably to a course of pleconaril treatment. Adverse effects were minimal and the drug was generally well-tolerated.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Child; Child, Preschool; Chronic Disease; Enterovirus; Enterovirus Infections; Follow-Up Studies; Humans; Infant, Newborn; Meningoencephalitis; Middle Aged; Oxadiazoles; Oxazoles; Treatment Outcome

Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection.. Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years).. Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different.. The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

Topics: Administration, Oral; Age Factors; Antiviral Agents; Area Under Curve; Biological Availability; Enterovirus Infections; Female; Humans; Infant, Newborn; Male; Oxadiazoles; Oxazoles

We describe the development, optimisation, and validation of an automated, cell-based and high-throughput screening assay using existing luminescence-based ATPlite reagents for identifying antiviral compounds that inhibit enterovirus replication. Antiviral efficacy was determined by measuring the ATP levels in cells that were protected from the viral cytopathic effect (CPE) by the antiviral compounds pleconaril and rupintrivir. CPE-based assay conditions were optimised at a cell density of 5000 cells/well and a viral infection dose of 100 CCID

Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Cytopathogenic Effect, Viral; Enterovirus; Enterovirus Infections; HeLa Cells; Humans; Isoxazoles; Luminescent Measurements; Microbial Sensitivity Tests; Oxadiazoles; Oxazoles; Phenylalanine; Pyrrolidinones; Valine; Vero Cells

4-dimethylamino benzoic acid (compound 12, synonym: 4EDMAB) was identified as an in vitro inhibitor of Coxsackie virus B3 (CVB3) replication in CPE-based assays (EC

Topics: Antiviral Agents; Capsid; Capsid Proteins; Cell Line; Cytopathogenic Effect, Viral; Drug Resistance, Viral; Drug Synergism; Enterovirus B, Human; Enterovirus Infections; Genotype; Humans; Molecular Conformation; Molecular Docking Simulation; Oxadiazoles; Oxazoles; para-Aminobenzoates; Protein Binding; RNA, Viral; Structure-Activity Relationship; Virus Replication

Enterovirus D68 (EV-D68) is a member of Picornaviridae and is a causative agent of recent outbreaks of respiratory illness in children in the United States. We report here the crystal structures of EV-D68 and its complex with pleconaril, a capsid-binding compound that had been developed as an anti-rhinovirus drug. The hydrophobic drug-binding pocket in viral protein 1 contained density that is consistent with a fatty acid of about 10 carbon atoms. This density could be displaced by pleconaril. We also showed that pleconaril inhibits EV-D68 at a half-maximal effective concentration of 430 nanomolar and might, therefore, be a possible drug candidate to alleviate EV-D68 outbreaks.

Topics: Antiviral Agents; Capsid; Child; Crystallography, X-Ray; Enterovirus D, Human; Enterovirus Infections; Humans; Hydrophobic and Hydrophilic Interactions; Oxadiazoles; Oxazoles; Respiratory Tract Diseases; United States; Viral Proteins

We investigated the susceptibility of 10 enterovirus D68 (EV-D68) isolates (belonging to clusters A, B, and C) to (entero)virus inhibitors with different mechanisms of action. The 3C-protease inhibitors proved to be more efficient than enviroxime and pleconaril, which in turn were more effective than vapendavir and pirodavir. Favipiravir proved to be a weak inhibitor. Resistance to pleconaril maps to V69A in the VP1 protein, and resistance to rupintrivir maps to V104I in the 3C protease. A structural explanation of why both substitutions may cause resistance is provided.

Topics: Antiviral Agents; Drug Resistance, Viral; Enterovirus D, Human; Enterovirus Infections; Humans; Microbial Sensitivity Tests; Models, Molecular; Oxadiazoles; Oxazoles; Receptors, Drug; Respiratory Tract Infections; Viral Proteins; Virus Replication

Enterovirus 71(EV71) causes recurring outbreaks of hand, foot and mouth disease and encephalitis leading to complications or death in young children. More effective antiviral drugs are needed to prevent or reduce EV71-related disease and complications. However, there are no standard models currently in use to evaluate activity against EV71 infection both in vitro and in vivo. In this study, the activity of ribavirin and pleconaril against EV71 infection was evaluated in two models. An in vitro EV71 infection model was developed in RD cells, and an in vivo EV71 infection model was applied. Ribavirin and pleconaril effectively increased the viability of infected cells. Pleconaril reduced the morbidity and mortality of one-day-old infected mice, but ribavirin did not protect the infected mice. In all, the results demonstrated that infected cells and infected mice can be used to evaluate antiviral activity of ribavirin and pleconaril against EV71 infection in vitro and in vivo.

Topics: Animals; Animals, Newborn; Antiviral Agents; Cell Line, Tumor; Cell Survival; Child, Preschool; Disease Models, Animal; Enterovirus A, Human; Enterovirus Infections; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Oxadiazoles; Oxazoles; Ribavirin; Survival Analysis

Human enteroviruses (HEVs) can cause severe infections, especially in patients with a deficient humoral immune response, such as X-linked agammaglobulinemia. In this patient group, chronic enteroviral meningitis (CEMA) is feared because of extensive morbidity and high fatality rate. Treatment options consist of intravenous immunoglobulin (IVIG), with various outcomes. Pleconaril is an antiviral agent with in vitro activity against HEVs that has been used in the treatment of HEV infections.. The efficacy of pleconaril and IVIG against HEV isolated from the patients was assessed in vitro in two patients with CEMA.. Echovirus 11 was found in the cerebrospinal fluid (CSF) of case 1. Treatment with high-dose IVIG and pleconaril did not provide any clinical improvement and HEV PCR in CSF remained positive. Case 2 (echovirus 13 positive in CSF) was also treated with IVIG and pleconaril. The patient recovered completely and HEV PCR in CSF became negative. Recent IVIG batches contained low titres of neutralizing antibodies against the patient strains. Echovirus 11 (case 1) was resistant to pleconaril in vitro, whereas echovirus 13 (case 2) was susceptible, in accordance with virological response after treatment and subsequent clinical results.. This is the first report that evaluates efficacy of antiviral treatment in CEMA patients in relation to in vitro susceptibility of clinical virus isolates. Since pleconaril is no longer available for compassionate use we strongly propagate that new drugs should be developed against these potential life threatening HEV infections.

Topics: Antiviral Agents; Cerebrospinal Fluid; Child; Chronic Disease; Drug Resistance, Viral; Enterovirus; Enterovirus Infections; Female; Humans; Immunoglobulins, Intravenous; Male; Meningoencephalitis; Microbial Sensitivity Tests; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Treatment Outcome

Amino acid 1092 (AA1092) in capsid protein 1 of coxsackievirus B3 (CVB3) is located in close vicinity to the central phenoxy group of capsid binders (i.e. pleconaril). Whereas isoleucine is associated with drug susceptibility, leucine and methionine confer resistance to pleconaril. In the present study, novel analogues with different substitutions in the central phenoxy group were synthesized to study their influence on anti-CVB3 activity with the aim to overcome pleconaril resistance. Two [(biphenyloxy)propyl]isoxazoles and pleconaril were synthesized without methyl groups in the central phenoxy ring using Suzuki coupling reaction and tested for antiviral activity against the pleconaril-resistant CVB3 Nancy. Furthermore, pleconaril with 3-methyl, 3-methoxy, 3-bromine, 2,3-dimethyl in the central ring as well as the external rings in meta position were synthesized for structure-activity relationship analysis with CVB3 variants containing leucine, methionine or isoleucine at position 1092, other coxsackieviruses B (CVB) as well as several rhinoviruses. The results demonstrate a high impact of substituents in the central ring of capsid inhibitors for anti-enteroviral activity. Pleconaril resistance of CVB3 based on Leu1092 or Met1092 was overcome by unsubstituted analogues or by monosubstitution with 3-methyl as well as 3-bromine in the central phenyl. The 3-bromine derivative inhibited a broad spectrum of CVB and rhinoviruses.

Topics: Antiviral Agents; Drug Design; Drug Resistance, Viral; Enterovirus B, Human; Enterovirus Infections; HeLa Cells; Humans; Isoxazoles; Mutation; Oxadiazoles; Oxazoles

We describe a case of fatal neonatal enteroviral infection caused by echovirus 7. Multiple treatments, including specific antiviral therapy, were attempted and failed. Studies of the viral isolate, maternal plasma, intravenous immunoglobulin preparations and pleconaril were performed to identify potential causes for treatment failure.

Topics: Antiviral Agents; Enterovirus B, Human; Enterovirus Infections; Fatal Outcome; Female; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Molecular Sequence Data; Oxadiazoles; Oxazoles; Sequence Analysis, DNA; Treatment Failure

At present, most promising compounds to treat enterovirus-induced diseases are broad-spectrum capsid function inhibitors which bind into a hydrophobic pocket in viral capsid protein 1 (VP1). Coxsackievirus B3 (CVB3) Nancy was the only prototypic enterovirus strain shown to be pleconaril-resistant. This study was designed to better understand the polymorphism of the hydrophobic pocket in CVB3 laboratory strains and clinical isolates and its implications for treatment with the capsid function inhibitor pleconaril.. Pleconaril susceptibility was determined in cytopathic effect-inhibitory, plaque reduction or virus yield assays. Sequence analysis of the genome region coding for VP1 and/or subsequent alignment of amino acids lining the hydrophobic pocket of five CVB3 laboratory strains and 20 clinical isolates were carried out. Virus chimeras and computational analysis were used to prove the role of amino acid 1092.. Despite high conservation of pocket amino acids, polymorphism was detected at positions 1092, 1094 and 1180. Neither Pro-1094-->Thr nor Val-1180-->Ile altered efficacy of pleconaril treatment. But the amino acid at position 1092 was strongly associated with susceptibility of CVB3 to the capsid inhibitor. Whereas leucine was involved in resistance, isoleucine and valine were detected in pleconaril-susceptible CVB3. Results from antiviral assays with hybrid viruses demonstrate the crucial role of amino acid 1092 in pleconaril susceptibility. A resistant cDNA-generated CVB3 became pleconaril-susceptible after accepting parts from the genome region encoding Ile-1092 into its capsid. Computational analysis suggests that conformational changes in the hydrophobic pocket occur when leucine is substituted for isoleucine or valine and that this change leads to susceptibility to pleconaril.

Topics: Amino Acid Substitution; Animals; Antiviral Agents; Capsid; Capsid Proteins; Cell Line; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Drug Resistance, Viral; Enterovirus B, Human; Enterovirus Infections; Humans; Hydrophobic and Hydrophilic Interactions; Oxadiazoles; Oxazoles; Polymorphism, Genetic

Chronic enteroviral meningoencephalitis (CEMA) is a rare complication of immunodeficient individuals and may present as insidious intellectual deterioration. Diagnosis requires isolation or PCR identification of enterovirus from the CSF. Pleconaril, a novel anti-picornaviral compound is available on a compassionate release basis to treat patients with potentially life threatening enteroviral infection. Non-invasive neuroimaging is an important new technique for both the diagnosis of encephalitis and as an objective assessment of response to treatment. We report two immunodeficient patients, one with common variable immunodeficiency and one with HIV, with an insidious presentation of CEMA. In both patients, perfusion single photon emission tomography scans were effective in monitoring treatment, correlating with clinical and virological response to pleconaril.

Topics: Adolescent; Adult; Antiviral Agents; Common Variable Immunodeficiency; Enterovirus; Enterovirus Infections; Female; HIV Infections; Humans; Immunocompromised Host; Male; Meningoencephalitis; Oxadiazoles; Oxazoles; Tomography, Emission-Computed, Single-Photon

A distinctive pattern of enterovirus 71 (EV71) infection, characterized by fever, exanthem, acute pulmonary edema (PE), brainstem encephalitis, and flaccid paresis, affects infants and young children. Most die rapidly owing to respiratory failure and fulminant PE.. The authors report short- and long-term outcome of six survivors of the acute illness.. In the context of acute PE and widespread weakness, recognition of the underlying neurologic disorder was facilitated by the distinctive pattern of MRI signal abnormalities in posterior pons and medulla. EV71-specific PCR of clinical samples helped confirm the diagnosis. Acute PE was managed with mechanical ventilation, afterload reduction, and inotrope support, and resolved completely over days. One patient with minimal neurologic recovery died 9 weeks after disease onset. The other patients have residual neurologic dysfunction, varying from subtle monoparesis to severe bulbar dysfunction, central and peripheral respiratory failure, and flaccid quadriparesis. Faster neurologic recovery was associated with less long-term deficit. Long-term outcome was similar in patients treated with and without pleconaril or IV immunoglobulin. Three long-term survivors treated with IV corticosteroids had less severe long-term neurologic disability than two not treated with steroids.. Acute pulmonary edema and encephalomyelitis occurs with EV71 infection in infants. Long-term neurologic outcome varied from minor, focal weakness to profound, global motor dysfunction with respiratory failure.

Topics: Acute Disease; Antiviral Agents; Child, Preschool; Combined Modality Therapy; Disease Outbreaks; Encephalitis, Viral; Enterovirus; Enterovirus Infections; Female; Follow-Up Studies; Humans; Immunoglobulins, Intravenous; Infant; Magnetic Resonance Imaging; Male; New South Wales; Oxadiazoles; Oxazoles; Pulmonary Edema; Survival Analysis; Survivors

During the Australian summer of 2000/2001, there was an outbreak of enterovirus 71 infection in Sydney. Between December 2000 and May 2001, approximately 200 children presented to Sydney Children's Hospital with hand-foot-and-mouth disease and 18 experienced neurologic complications. Four presented with acute invasive central nervous system disease and severe pulmonary edema. We describe the cardiorespiratory disturbances and intensive care management of these four consecutive children successfully treated for neurogenic pulmonary edema attributed to proven enterovirus 71 infection. All four survived the acute stage of the illness. However, all four have been left with significant debilitating morbidity. Epidemic enterovirus 71 brainstem encephalitis presenting as neurogenic pulmonary edema can be successfully managed in the pediatric intensive care unit but has great potential to yield a large number of handicapped toddlers and become "the poliomyelitis of the 21st century."

Topics: Antiviral Agents; Child, Preschool; Echocardiography; Encephalitis, Viral; Enterovirus; Enterovirus Infections; Female; Follow-Up Studies; Humans; Infant; Intensive Care Units, Pediatric; Magnetic Resonance Imaging; Male; Oxadiazoles; Oxazoles; Pulmonary Edema; Respiration, Artificial; Time Factors

Two patients with severe combined immunodeficiency and enterovirus infections were successfully treated with pleconaril. There were no adverse affects.

Topics: Antiviral Agents; Enterovirus Infections; Feces; Female; Humans; Infant; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; RNA, Viral; Severe Combined Immunodeficiency

Pleconaril (VP-63843) 3-[3,5-dimethyl-4[[3-(3-methyl-5-isoxazolyl)propyl] oly]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole is a novel, broad spectrum antipicornaviral agent. Pleconaril binds to a hydrophobic pocket in the viral capsid inducing conformational changes, which lead to altered receptor binding and viral uncoating. Pleconaril is orally bioavailable and achieves serum concentrations in excess of those required to inhibit 90% of clinical rhino- and enteroviral isolates in vitro. It possesses the additional advantage of achieving several fold higher concentrations within the central nervous system and nasal secretions than in serum, a characteristic that is highly desirable for an antiviral targeted towards viruses known to cause central nervous system and upper respiratory tract infections. Approximately 80% of an orally administered dose is excreted in the faeces within 48 h. Urine excretion accounts for the remainder of the drug. Pleconaril has demonstrated an excellent safety profile in dose escalation and clinical studies. Clinical studies have reported a reduction in the duration and intensity of symptoms in children and adults with enteroviral meningitis and in adults with rhinoviral respiratory tract infections treated with pleconaril. Lastly, pleconaril has demonstrated efficacy in the treatment of severe life-threatening enteroviral infections of the newborn and in immunosuppressed individuals. Pleconaril appears to be a promising drug for the treatment of enteroviral and rhinoviral infections.

Topics: Antiviral Agents; Clinical Trials as Topic; Enterovirus Infections; Humans; Oxadiazoles; Oxazoles

Topics: Antiviral Agents; Child; Diagnosis, Differential; Enterovirus Infections; Humans; Oxadiazoles; Oxazoles; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral