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Vadim Makarov - One of the best experts on this subject based on the ideXlab platform.

  • the evolution of Pleconaril modified o alkyl linker analogs have biological activity towards coxsackievirus b3 nancy
    2020
    Co-Authors: Alexandrina Volobueva, Anna Egorova, Sean Ekins, Anastasia V Galochkina, Viktorovich Vladimir Zarubaev, Vadim Makarov
    Abstract:

    Coxsackieviruses type B are one of the most common causes of mild upper respiratory and gastrointestinal illnesses. At the time of writing, there are no approved drugs for effective antiviral treatment for Coxsackieviruses type B. We used the core-structure of Pleconaril, a well-known antienteroviral drug candidate, for the synthesis of novel compounds with O-propyl linker modifications. Some original compounds with 4 different linker patterns, such as sulfur atom, ester, amide, and piperazine, were synthesized according to five synthetic schemes. The cytotoxicity and bioactivity of 14 target compounds towards Coxsackievirus B3 Nancy were examined. Based on the results, the values of 50% cytotoxic dose (CC50), 50% virus-inhibiting dose (IC50), and selectivity index (SI) were calculated for each compound. Several of the novel synthesized derivatives exhibited a strong anti-CVB3 activity (SI > 20 to > 200). These results open up new possibilities for synthesis of further new selective anticoxsackievirus compounds.

  • novel Pleconaril derivatives influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses
    2020
    Co-Authors: Anna Egorova, Vadim Makarov, Elena Kazakova, Birgit Jahn, Sean Ekins, Michaela Schmidtke
    Abstract:

    Abstract Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel Pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of Pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against Pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against Pleconaril-resistant as well as Pleconaril-susceptible enteroviruses with IC50 values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than Pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations.

  • cryo em structure of Pleconaril resistant rhinovirus b5 complexed to the antiviral obr 5 340 reveals unexpected binding site
    2019
    Co-Authors: Jiri Wald, Vadim Makarov, Marion Pasin, Martina Richter, Christin Walther, Neann Mathai, Johannes Kirchmair, Nikolaus Goessweinermohr
    Abstract:

    Viral inhibitors, such as Pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed pyrazolopyrimidines inhibit Pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of Pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally Pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 A with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 A, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 A was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.

  • new Pleconaril and biphenyloxy propyl isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against Pleconaril resistant coxsackievirus b3
    2009
    Co-Authors: Michaela Schmidtke, Romy Zieger, Olga B Riabova, Peter Wutzler, Vadim Makarov
    Abstract:

    Abstract 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.

  • susceptibility of coxsackievirus b3 laboratory strains and clinical isolates to the capsid function inhibitor Pleconaril antiviral studies with virus chimeras demonstrate the crucial role of amino acid 1092 in treatment
    2005
    Co-Authors: Michaela Schmidtke, Olga B Riabova, Vadim Makarov, Elke Hammerschmidt, Susanne Schuler, Eckhard Birchhirschfeld, Roland Zell, Peter Wutzler
    Abstract:

    OBJECTIVES: 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. METHODS: 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. RESULTS AND CONCLUSIONS: 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.

A D B Webster - One of the best experts on this subject based on the ideXlab platform.

  • Pleconaril an advance in the treatment of enteroviral infection in immuno compromised patients
    2005
    Co-Authors: A D B Webster
    Abstract:

    1. Discovery of Pleconaril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Anti-viral mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 4. Enteroviral disease in immunocompromised patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

  • Pleconaril an advance in the treatment of enteroviral infection in immuno compromised patients
    2005
    Co-Authors: A D B Webster
    Abstract:

    Human papillomaviruses (HPVs) are formally described by isolation of their circular double-stranded DNA genomes and establishment and comparison of the nucleotide sequence of these genomes. Alternatives such as serological diagnosis and maintenance of HPVs in culture are neither clinically useful nor consistently feasible. Novel HPV isolates have traditionally been described as “types”. The analysis of specific HPV types is of medical importance, because HPV types typically induce type-specific lesions, i.e. they may be specific for cutaneous or mucosal epithelia, or give rise to benign warts or malignant carcinomas. Recently, it was formally decided that papillomaviruses are a virus family separate from the polyomaviruses. Within the papillomavirus family, closely or remotely related types form species or genera. These formal agreements were important as they brought the taxonomy of papillomaviruses in line with that of other viruses, bacteria and higher organisms, although their impact on medical practice and terminology used in clinical studies is limited. Notably, however, HPV types that are closely related (i.e. form “species”) are associated with similar lesions. Confusion of the terms “type” and “subtype” should be avoided, as the latter term refers to some specific but rare taxonomic assemblages. In contrast to many RNA viruses, HPV types evolve very slowly, and diverged since the origin of humans only by about 2%. These divergent isolates are called “variants”. HPVs evolved together with humankind and Homo sapiens was never without HPVs, and consequently never without warts and cervical cancer. Variants of the same HPV type may have different pathogenicity and may account for part of the worldwide disparities in the occurrence of genital cancers.

  • spect scans for monitoring response to Pleconaril therapy in chronic enteroviral meningoencephalitis
    2003
    Co-Authors: V J Tormey, John R Buscombe, A P J Thomson, Margaret Johnson, A D B Webster
    Abstract:

    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.

Michaela Schmidtke - One of the best experts on this subject based on the ideXlab platform.

  • novel Pleconaril derivatives influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses
    2020
    Co-Authors: Anna Egorova, Vadim Makarov, Elena Kazakova, Birgit Jahn, Sean Ekins, Michaela Schmidtke
    Abstract:

    Abstract Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel Pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of Pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against Pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against Pleconaril-resistant as well as Pleconaril-susceptible enteroviruses with IC50 values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than Pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations.

  • new Pleconaril and biphenyloxy propyl isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against Pleconaril resistant coxsackievirus b3
    2009
    Co-Authors: Michaela Schmidtke, Romy Zieger, Olga B Riabova, Peter Wutzler, Vadim Makarov
    Abstract:

    Abstract 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.

  • failure of Pleconaril to inhibit the infectivity of theiler s murine encephalomyelitis virus in l cells
    2009
    Co-Authors: Doris Porombka, Dirk Schaudien, Michaela Schmidtke, Peter Wutzler, Wolfgang Baumgartner
    Abstract:

    Theiler's murine encephalomyelitis virus (TMEV) infection of L cells results in a cytopathic effect (CPE) characterised by cell death and the formation of small plaques. The potential of Pleconaril, a novel broad―spectrum capsid function inhibitor that blocks effectively the replication of most rhino― and enteroviruses, to inhibit the replication of TMEV was investigated using a plaque reduction assay. L cells were infected with 10 -5 or 10 -6 TCID 50 /ml of the laboratory BeAn strain of TMEV supplemented with defined log 2 dilutions of Pleconaril. No significant dose depended reduction of the plaque numbers was seen. This study demonstrated the inability of Pleconaril to inhibit the infection of L cells with the BeAn strain of TMEV which is in contrast to previous studies that showed that Pleconaril inhibits the replication of other picornaviruses.

  • susceptibility of coxsackievirus b3 laboratory strains and clinical isolates to the capsid function inhibitor Pleconaril antiviral studies with virus chimeras demonstrate the crucial role of amino acid 1092 in treatment
    2005
    Co-Authors: Michaela Schmidtke, Olga B Riabova, Vadim Makarov, Elke Hammerschmidt, Susanne Schuler, Eckhard Birchhirschfeld, Roland Zell, Peter Wutzler
    Abstract:

    OBJECTIVES: 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. METHODS: 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. RESULTS AND CONCLUSIONS: 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.

  • Novel [(biphenyloxy)propyl]isoxazole derivatives for inhibition of human rhinovirus 2 and coxsackievirus B3 replication
    2005
    Co-Authors: Vadim Makarov, Olga B Riabova, Vladimir G. Granik, Peter Wutzler, Michaela Schmidtke
    Abstract:

    Objectives: During this study, novel biphenyl derivatives were synthesized and tested for antiviral activity. Methods: A new method based on the Suzuki coupling reaction has been established for the synthesis of these polysubstituted chain systems. In parallel with cytotoxicity, the antiviral activity of biphenyl derivatives has been determined in cytopathic effect (CPE)-inhibitory assays with the Pleconaril-resist-ant coxsackievirus B3 (CVB3) strain Nancy, human rhinovirus 2 (HRV-2) and 14 (HRV-14) and in plaque reduction assays with the Pleconaril-sensitive human isolate CVB3 97-927 in HeLa cells. Based on the results from these investigations the selectivity index (SI) was determined as, the ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration. Results: The new method based on the Suzuki coupling reaction includes the condensation of 2,6-dimethyl-4-bromophenol with pentyne chloride by means of potassium carbonate and potassium iodide in N-methylpyrrolidone-2 and yields 5-bromo-1,3-dimethyl-2-(4-pentynyloxy)benzene. Its condensation with methylacetaldoxime results in 3-methylisoxazole derivatives. The following reaction with different benzeneboronic acids by means of tetrakis(triphenylphosphine)-pallladium(0) finally yields the corresponding derivatives. Several of the novel synthesized derivatives demonstrated a good antiviral activity on CVB3 (SI > 2 to > 37.5) and a strong anti-HRV-2 activity (SI >50 to > 200). In contrast, none of the compounds inhibited the HRV-14-induced CPE. Conclusions: These results indicate that [(biphenyloxy)propyl]isoxazole derivatives are potential inhibitors of HRV-2 and CVB3 replication, and make them promising agents for the specific treatment of these virus infections.

Gregory L Kearns - One of the best experts on this subject based on the ideXlab platform.

  • single dose pharmacokinetics of Pleconaril in neonates
    2000
    Co-Authors: Gregory L Kearns, Richard F Jacobs, Edmund V Capparelli, Kathy M Johnson, John S. Bradley, Laura P James, Susan M Abdelrahman
    Abstract:

    Background. 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. Methods. 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). Results. 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 (C max 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 ClIF 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 C max (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. Conclusions. 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.

  • single oral dose escalation pharmacokinetics of Pleconaril vp 63843 capsules in adults
    1999
    Co-Authors: Susan M Abdelrahman, Gregory L Kearns
    Abstract:

    : Pleconaril is an orally active broad-spectrum antipicornaviral agent with excellent penetration into the central nervous system and nasal epithelium. The authors report the results of a randomized, placebo-controlled, dose escalation study of Pleconaril oral capsules following single-dose administration of 50 to 1000 mg. Fifty-six healthy adults (ages 19-55) participated in the study. Each subject received a single dose of Pleconaril oral capsule(s) or an identically matched placebo. Blood samples (n = 19) were obtained over 36 hours postdose, and Pleconaril was quantified from plasma by gas chromatography. Pleconaril disposition was best characterized using a two-compartment open-model with first-order absorption. Fifty-five subjects completed the study (31 +/- 10 years, 77.6 +/- 11 kg). The administration of Pleconaril was well tolerated. There was no difference in tmax, lambda z, ka, t1/2elim, Cl/F, or Vdss/F among the various dose groups. A significant difference in both Cmax and AUC was observed between study groups; however, this difference became insignificant when the parameters were corrected for dose. Cmax and AUC were dose proportional between 50 and 1000 mg (r2 > 0.97 and 0.90, respectively). Pleconaril demonstrates a favorable safety and pharmacokinetic profile following single-dose administration.

  • single dose pharmacokinetics of a Pleconaril vp63843 oral solution in children and adolescents
    1999
    Co-Authors: Gregory L Kearns, Susan M Abdelrahman, Richard F Jacobs, Douglas L Blowey, Thomas G Wells, James D Marshall, Laura P James
    Abstract:

    Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of Pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 6 3.1 years) received a single 5-mg/kg of body weight oral dose of Pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n 5 10) were obtained over 24 h postdose, and Pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight 5 1/Ycalc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma Pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means 6 standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (Cmax) was 1,272.5 6 622.1 ng/ml. The time to Cmax was 4.1 6 1.5 h, and the lag time was 0.75 6 0.56 h. The apparent absorption rate constant was 0.75 6 0.48 1/h, and the elimination rate constant was 0.16 6 0.07 1/h. The area under the concentrationtime curve from 0 to 24 h was 8,131.15 6 3,411.82 ng z h/ml. The apparent total plasma clearance was 0.81 6 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 6 2.02 liters/kg. The mean elimination half-life of Pleconaril was 5.7 h. The mean plasma Pleconaril concentrations at both 12 h (250.4 6 148.2 ng/ml) and 24 h (137.9 6 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit >90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of Pleconaril for therapeutic trials in pediatric patients with enteroviral infections.

  • single dose pharmacokinetics of a Pleconaril vp63843 oral solution and effect of food
    1998
    Co-Authors: Susan M Abdelrahman, Gregory L Kearns
    Abstract:

    Pleconaril is an orally active broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (200 mg) of Pleconaril oral solution in fed and fasting humans. Twelve healthy adult subjects (18.7 to 39 years of age) participated in this study. Each subject received a single 200-mg dose of Pleconaril oral solution, both coadministered with a standard English breakfast and following a 10-h predose fast. There was a minimum 7-day washout period between Pleconaril doses. Repeated blood samples (n = 10) were obtained over 24 h postdose, and the Pleconaril level in plasma was quantified by gas chromatography. Plasma concentration-versus-time data were curve fitted for each subject by using a nonlinear weighted least-squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. Pleconaril disposition was best characterized by a one-compartment open model with first-order absorption. The apparent bioavailability of Pleconaril oral solution was significantly increased with the administration of food. The area under the concentration-time curve and maximum concentration of Pleconaril in plasma achieved following the standard English breakfast (i.e., 9.08 +/- 3.23 mg/liter . h and 1.14 +/- 0.58 mg/liter, respectively) were 2.2- and 2.5-fold higher, respectively than those achieved in the fasting state (i.e., 4.08 +/- 2.74 mg/liter . h and 0.46 +/- 0.30 mg/liter, respectively). Mean plasma Pleconaril concentrations 12 h after a single 200-mg oral dose (fed, 0.25 +/- 0.2 mg/liter; fasting, 0.11 +/- 0.10 mg/liter) in healthy adults remained greater than that required to inhibit more than 90% of the enteroviruses in cell culture (i.e., 0.07 mg/liter). To enhance the oral bioavailability of Pleconaril, coadministration with a fat-containing meal is recommended.

Daniel C Pevear - One of the best experts on this subject based on the ideXlab platform.

  • insights into the genetic basis for natural phenotypic resistance of human rhinoviruses to Pleconaril
    2005
    Co-Authors: Rebecca M Ledford, Marc S Collett, Daniel C Pevear
    Abstract:

    Abstract Recent phylogenetic analyses of the deduced amino acid sequence of the major viral capsid protein (VP1) of all human rhinovirus (HRV) serotypes revealed two distinct species within the genus: species A (75 serotypes) and species B (25 serotypes). Pleconaril is a novel capsid inhibitor of HRVs. All 75 species A serotypes and 18 of the 25 species B serotypes are susceptible to inhibition by Pleconaril in cell culture. The seven resistant serotypes are HRV-4, -5, -42, -84, -93, -97 and -99. We were interested in understanding the genetic basis for phenotypic resistance to Pleconaril among these naturally occurring viruses. We compared the 25 amino acids of VP1 that comprise the drug-binding pocket of susceptible and resistant species B viruses. A consistent difference was observed at two positions: the vast majority of susceptible viruses had tyrosine and valine at VP1 residues 152 and 191, respectively (Y 152 and V 191 ); all resistant viruses had phenylalanine and leucine at these positions (F 152 and L 191 ). HRV-14, a Pleconaril susceptible virus, has a drug-binding pocket amino acid composition that differs from the naturally resistant HRV-5 and HRV-42 only at these two positions. To gain further insight into the role of these specific residues in natural resistance to Pleconaril, we substituted the amino acids at these two positions individually and in combination in an infectious clone of HRV-14 and tested the rescued virus for susceptibility to Pleconaril and virion stability. The results indicate that substitution of V 191 to Leu in HRV-14 has a profound negative impact on drug susceptibility but that full resistance to Pleconaril is only seen when combined with Phe at position 152 in a HRV-14 double variant (F 152 , L 191 ). These data identify L 191 in species B HRV as a potentially key residue in conferring significantly reduced susceptibility to Pleconaril. These results may be useful in distinguishing naturally occurring viral resistance to Pleconaril from treatment-emergent resistance.

  • relationship of Pleconaril susceptibility and clinical outcomes in treatment of common colds caused by rhinoviruses
    2005
    Co-Authors: Daniel C Pevear, Mark A Mckinlay, Tina M Demenczuk, Linda R Barone, Frederick G Hayden, Marc S Collett
    Abstract:

    Pleconaril, a specific inhibitor of human picornaviruses, showed therapeutic efficacy against community-acquired colds caused by rhinoviruses in two placebo-controlled trials. Virological assessments were conducted during these trails, including virus culture and drug susceptibility testing. Nasal mucus samples collected from the enrolled patients were tested for the presence of picornavirus by reverse transcriptase PCR and culture. In total, 827 baseline nasal mucus samples were positive by virus culture (420 in the placebo group and 407 in the Pleconaril group). Pleconaril treatment was associated with a more rapid loss of culturable virus. By study day 3, the number of samples positive by culture fell to 282 for the placebo-treated subjects and 202 for the Pleconaril-treated subjects (P 0.38 μg/ml did not benefit from Pleconaril treatment. These results indicate that the magnitude of symptomatic improvement in Pleconaril-treated subjects with community-acquired colds is related to the drug susceptibility of the infecting virus, clearly linking the antiviral effects of the drug to clinical efficacy. Postbaseline virus isolates with reduced susceptibility or full resistance to Pleconaril were recovered from 10.7% and 2.7% of drug-treated subjects, respectively. These patients shed low levels of virus and had no unusual clinical outcomes. Nevertheless, studies on the biologic properties and transmissibility of these variant viruses are warranted.

  • vp1 sequencing of all human rhinovirus serotypes insights into genus phylogeny and susceptibility to antiviral capsid binding compounds
    2004
    Co-Authors: Rebecca M Ledford, Marc S Collett, Tina M Demenczuk, Adiba Watanyar, Nitesh R Patel, Torsten Herbertz, Daniel C Pevear
    Abstract:

    Rhinoviruses are the most common infectious agents of humans. They are the principal etiologic agents of afebrile viral upper-respiratory-tract infections (the common cold). Human rhinoviruses (HRVs) comprise a genus within the family Picornaviridae . There are >100 serotypically distinct members of this genus. In order to better understand their phylogenetic relationship, the nucleotide sequence for the major surface protein of the virus capsid, VP1, was determined for all known HRV serotypes and one untyped isolate (HRV-Hanks). Phylogenetic analysis of deduced amino acid sequence data support previous studies subdividing the genus into two species containing all but one HRV serotype (HRV-87). Seventy-five HRV serotypes and HRV-Hanks belong to species HRV-A, and twenty-five HRV serotypes belong to species HRV-B. Located within VP1 is a hydrophobic pocket into which small-molecule antiviral compounds such as Pleconaril bind and inhibit functions associated with the virus capsid. Analyses of the amino acids that constitute this pocket indicate that the sequence correlates strongly with virus susceptibility to Pleconaril inhibition. Further, amino acid changes observed in reduced susceptibility variant viruses recovered from patients enrolled in clinical trials with Pleconaril were distinct from those that confer natural phenotypic resistance to the drug. These observations suggest that it is possible to differentiate rhinoviruses naturally resistant to capsid function inhibitors from those that emerge from susceptible virus populations as a result of antiviral drug selection pressure based on sequence analysis of the drug-binding pocket.

  • efficacy and safety of oral Pleconaril for treatment of colds due to picornaviruses in adults results of 2 double blind randomized placebo controlled trials
    2003
    Co-Authors: Frederick G Hayden, Darrell T Herrington, Teresa L Coats, Ellen C Cooper, Stephen Villano, Spencer Hudson, Daniel C Pevear, Marc S Collett, Mark A Mckinlay
    Abstract:

    : The novel capsid-binding antiviral Pleconaril inhibits in vitro replication of most rhinoviruses and enteroviruses. Oral Pleconaril treatment was studied in 2 parallel randomized, double-blind, placebo-controlled trials. Among 1363 picornavirus-infected participants (65%) in the studies combined, the median time to alleviation of illness was 1 day shorter for Pleconaril recipients than for placebo recipients (P<.001). Cold symptom scores and frequency of picornavirus cultured from nasal mucus specimens were lower among Pleconaril recipients by day 2 of treatment. No treatment effects were seen in those without picornavirus infection. Pleconaril was associated with a higher incidence of nausea (6% vs. 4%) and diarrhea (9% vs. 7%) and with small increases in mean serum cholesterol levels and platelet counts, compared with baseline measurements. A subsequent 6-week prophylaxis study found that Pleconaril induces cytochrome P-450 3A enzymes, which metabolize a variety of drugs, including ethinyl estradiol. Early Pleconaril treatment was well tolerated and significantly reduced the duration and severity of colds due to picornaviruses in adults.

  • activity of Pleconaril against enteroviruses
    1999
    Co-Authors: Daniel C Pevear, Tina M Tull, Martin Seipel, James M Groarke
    Abstract:

    The activity of Pleconaril in cell culture against prototypic enterovirus strains and 215 clinical isolates of the most commonly isolated enterovirus serotypes was examined. The latter viruses were isolated by the Centers for Disease Control and Prevention during the 1970s and 1980s from clinically ill subjects. Pleconaril at a concentration of ≤0.03 μM inhibited the replication of 50% of all clinical isolates tested. Ninety percent of the isolates were inhibited at a drug concentration of ≤0.18 μM. The most sensitive serotype, echovirus serotype 11, was also the most prevalent enterovirus in the United States from 1970 to 1983. Pleconaril was further tested for oral activity in three animal models of lethal enterovirus infection: coxsackievirus serotype A9 infection in suckling mice, coxsackievirus serotype A21 strain Kenny infection in weanling mice, and coxsackievirus serotype B3 strain M infection in adult mice. Treatment with Pleconaril increased the survival rate in all three models for both prophylactic and therapeutic dosing regimens. Moreover, Pleconaril dramatically reduced virus levels in target tissues of coxsackievirus serotype B3 strain M-infected animals. Pleconaril represents a promising new drug candidate for potential use in the treatment of human enteroviral infections.