Pleconaril was originally developed by Sanofi-Aventis, and licensed to ViroPharma in 1997. ViroPharma developed it further, and submitted a New Drug Application to the United StatesFood and Drug Administration (FDA) in 2001. The application was rejected, citing safety concerns; and ViroPharma re-licensed it to Schering-Plough in 2003. The Phase II clinical trial was completed in 2007.[2] A pleconaril intranasal spray had reached phase II clinical trial for the treatment of the common cold symptoms and asthma complications. However, the results have yet to be reported.[6]
Mechanism of action
In enteroviruses, Pleconaril prevents the virus from exposing its RNA, and in rhinoviruses Pleconaril prevents the virus from attaching itself to the host cell.[7] Human rhinoviruses (HRVs) contain four structural proteins labeled VP1-VP4. Proteins VP1, VP2 and VP3 are eight stranded anti-parallel β-barrels. VP4 is an extended polypeptide chain on the viral capsid inner surface.[8] Pleconaril binds to a hydrophobic pocket in the VP1 protein. Pleconaril has been shown in viral assembly to associate with viral particles.[9] Through noncovalent, hydrophobic interactions compounds can bind to the hydrophobic pocket.[10] Amino acids in positions Tyr152 and Val191 are a part of the VP1 drug binding pocket.[8]
This Image was created in JMOL showing the beta sheets and alpha helices of the Human Rhinovirus. The molecule embedded in the hydrophobic pocket of the VP1 protein is Pleconaril
In Coxsackievirus, Pleconaril efficiency correlates to the susceptibility of CVB3 with the amino acid at position 1092 in the hydrophobic pocket.[11] Amino acid 1092 is in close proximity to the central ring of capsid binders.[12] The binding of pleconaril in the hydrophobic pocket creates conformational changes, which increases the rigidity of the virion and decreases the virions' ability to interact with its receptor.[13] Drugs bind with the methylisoxazole ring close to the entrance pocket in VP1, the 3-fluromethyl oxadiazole ring at the end of the pocket and the phenyl ring in the center of the pocket.[6]
Clinical trials
The results of two randomized, double blind, placebo studies found Pleconaril treatment could benefit patients with colds due to picornaviruses.[14] Participants in the studies were healthy adults from Canada and the United States, with self-diagnosed colds that had occurred within 24 hours of trial enrollment. Participants were randomly given a placebo or two 200 mg tablets to take three times daily for five days. To increase absorption it was recommended to be taken after a meal.[14] To monitor the effectiveness of Pleconaril, participants recorded the severity of their symptoms and nasal mucosal samples were obtained at enrollment, day 3, day 6 and day 18. The two studies had a total of 2096 participants and more than 90% (1945) completed the trial. The most common reason for a participant not finishing the trial was an adverse event. Pleconaril treatment showed a reduction in nose blowing, sleep disturbance, and less cold medication used.[14]
Another study showed over 87% of virus isolates in cell culture were inhibited by pleconaril.[9] Virus variants were detected in 0.7% of the placebo group and 10.7% of the pleconaril group. Of the two isolates a subject from the placebo group had a resistant virus in cell culture to pleconaril. The other strain was susceptible to the drug. The pleconaril group had 21 virus strains, which remained susceptible. Resistance strains were found in 7 pleconaril patients.[9]
A Phase II study that used an intranasal formulation of pleconaril failed to show a statistically significant result for either of its two primary efficacy endpoints, percentage of participants with rhinovirus PCR-positive colds and percentage of participants with asthma exacerbations together with rhinovirus-positive PCR.[15]
Resistance
In human rhinoviruses mutations in amino acids at positions 152 and 191 decrease the efficiency of pleconaril. The resistant HRV have phenylalanine at position 152 and leucine at position 191. In vitro studies have shown resistance to pleconaril may emerge. The wild type resistance frequency to pleconaril was about 5×10−5. Coxsackievirus B3(CVB3) strain Nancy and other mutants carry amino acid substitutions at position 1092 of Ile1092->Leu1092 or Ile1092->Met in VP1. The Ile->Leu mutation causes complete resistance to pleconaril. The study found resistance of CVB3 to pleconaril can be overcome by substitution of the central phenyl group. Methyl and bromine substitutions created an increase of pleconaril activity towards sensitive and resistant strains. Amino acid substitutions in the hydrophobic pocket and receptor binding region of viral capsid proteins were shown to have an effect against the sensitivity of capsid binding antivirals.[6]
Side effects of pleconaril
The U.S. Food and Drug Administration rejected pleconaril in 2002 due to the side effects. The most commonly reported side effects were mild to moderate headache, diarrhea, and nausea.[14] Some women were having symptoms of spotting in between periods. Menstrual irregularities were reported by 3.5% of the 320 pleconaril treated women using oral contraceptives and by none of the 291 placebo treated women.[14] In the clinical trial two women became pregnant due to the drug interfering with hormonal birth control by activation of cytochrome P-450 3A enzymes. Other patients have described painful nasal inflammation.[16]
^ ab"Effects of Pleconaril Nasal Spray on Common Cold Symptoms and Asthma Exacerbations Following Rhinovirus Exposure (Study P04295AM2)". ClinicalTrials.gov. U.S. National Institutes of Health. March 2007. Retrieved 2007-04-10.
^Pevear D, Tull T, Seipel M, Groarke J (1999). "Activity of pleconaril against enteroviruses". Antimicrob Agents Chemother. 43 (9): 2109–15. doi:10.1128/AAC.43.9.2109. PMC89431. PMID 10471549.
^Ronald B. Turner; J. Owen Hendley (2005). "Virucidal hand treatments for prevention of rhinovirus infection". J Antimicrob Chemother. 56 (5): 805–807. doi:10.1093/jac/dki329. PMID 16159927.
^Liu, Y; et al. (2015). "Structure and inhibition of EV-D68, a virus that causes respiratory illness in children". Science. 347 (6217): 71–74. Bibcode:2015Sci...347...71L. doi:10.1126/science.1261962. PMC4307789. PMID 25554786.
^ abcSchmidtke, Michaela; Wutzler, Peter; Zieger, Romy; Riabova, Olga B.; Makarov, Vadim A. (2009). "New pleconaril and [(biphenyloxy)propyl]isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against pleconaril-resistant coxsackievirus B3". Antiviral Research. 81 (1): 56–63. doi:10.1016/J.ANTIVIRAL.2008.09.002. PMID 18840470.
^Florea N, Maglio D, Nicolau D (2003). "Pleconaril, a novel antipicornaviral agent". Pharmacotherapy. 23 (3): 339–48. doi:10.1592/phco.23.3.339.32099. PMC7168037. PMID 12627933. Free full text with registration
^ abLedford, Rebecca M.; Collett, Marc S.; Pevear, Daniel C. (1 December 2005). "Insights into the genetic basis for natural phenotypic resistance of human rhinoviruses to pleconaril". Antiviral Research. 68 (3): 135–138. doi:10.1016/j.antiviral.2005.08.003. PMID 16199099.
^ abcPevear, D. C.; Hayden, F. G.; Demenczuk, T. M.; Barone, L. R.; McKinlay, M. A.; Collett, M. S. (26 October 2005). "Relationship of Pleconaril Susceptibility and Clinical Outcomes in Treatment of Common Colds Caused by Rhinoviruses". Antimicrobial Agents and Chemotherapy. 49 (11): 4492–4499. doi:10.1128/AAC.49.11.4492-4499.2005. PMC1280128. PMID 16251287.
^Rotbart, HA (February 2002). "Treatment of picornavirus infections". Antiviral Research. 53 (2): 83–98. doi:10.1016/s0166-3542(01)00206-6. PMID 11750935.
^Braun, Heike; Makarov, Vadim A.; Riabova, Olga B.; Wutzler, Peter; Schmidtke, Michaela (2011). "Amino Acid Substitutions At Residue 207 of Viral Capsid Protein 1 (VP1) Confer Pleconaril Resistance in Coxsackievirus B3 (CVB3)". Antiviral Research. 90 (2): A54–A55. doi:10.1016/j.antiviral.2011.03.100.
^Schmidtke, Michaela; Wutzler, Peter; Zieger, Romy; Riabova, Olga B.; Makarov, Vadim A. (2009). "New pleconaril and [(biphenyloxy)propyl]isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against pleconaril-resistant coxsackievirus B3". Antiviral Research. 81 (1): 56–63. doi:10.1016/j.antiviral.2008.09.002. PMID 18840470.
^Thibaut, Hendrik Jan; De Palma, Armando M.; Neyts, Johan (2012). "Combating enterovirus replication: State-of-the-art on antiviral research". Biochemical Pharmacology. 83 (2): 185–192. doi:10.1016/j.bcp.2011.08.016. PMID 21889497.
^ abcdeHayden, F.G.; Herrington, D.T.; Coats, T.L.; Kim, K.; Cooper, E.C.; Villano, S.A.; Liu, S.; Hudson, S.; Pevear, D.C.; Collett, M.; McKinlay, M. (Jun 15, 2003). "Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of 2 double-blind, randomized, placebo-controlled trials". Pleconaril Respiratory Infection Study, Group. Clinical Infectious Diseases. 36 (12): 1523–32. doi:10.1086/375069. PMC7199898. PMID 12802751.
^National Institutes of Health. Effects of Pleconaril Nasal Spray on Common Cold Symptoms and Asthma Exacerbations Following Rhinovirus Exposure (Study P04295AM2). Clinical Trials.gov. Available at http://www.clinicaltrials.gov/ct/gui/show/NCT00394914. Accessed: July 20, 2015
^Greenwood, Veronique (2011). "Curing the Common Cold". Scientific American. 304 (1): 30–1. Bibcode:2011SciAm.304a..30G. doi:10.1038/scientificamerican0111-30. PMID 21265321. Retrieved 2013-03-25.
January 08, 2023
pleconaril, picovir, antiviral, drug, that, being, developed, schering, plough, prevention, asthma, exacerbations, common, cold, symptoms, patients, exposed, picornavirus, respiratory, infections, administered, either, orally, intranasally, active, against, vi. Pleconaril Picovir 1 is an antiviral drug that was being developed by Schering Plough for prevention of asthma exacerbations and common cold symptoms in patients exposed to picornavirus respiratory infections 2 Pleconaril administered either orally or intranasally is active against viruses in the Picornaviridae family including Enterovirus 3 and Rhinovirus 4 It has shown useful activity against the dangerous enterovirus D68 5 PleconarilClinical dataRoutes ofadministrationOral intranasalATC codeJ05AX06 WHO Legal statusLegal status Pharmacokinetic dataBioavailability70 oral Protein binding gt 99 MetabolismHepaticExcretion lt 1 excreted unchanged in urineIdentifiersIUPAC name 3 3 5 dimethyl 4 3 3 methylisoxazol 5 yl propoxy phenyl 5 trifluoromethyl 1 2 4 oxadiazoleCAS Number153168 05 9 NPubChem CID1684DrugBankDB05105 NChemSpider1621 YUNII9H4570Q89DChEMBLChEMBL29609 YPDB ligandW11 PDBe RCSB PDB CompTox Dashboard EPA DTXSID8057649ECHA InfoCard100 208 947Chemical and physical dataFormulaC 18H 18F 3N 3O 3Molar mass381 355 g mol 13D model JSmol Interactive imageSMILES FC F F c1nc no1 c3cc c OCCCc2onc c2 C c c3 C CInChI InChI 1S C18H18F3N3O3 c1 10 7 13 16 22 17 27 24 16 18 19 20 21 8 11 2 15 10 25 6 4 5 14 9 12 3 23 26 14 h7 9H 4 6H2 1 3H3 YKey KQOXLKOJHVFTRN UHFFFAOYSA N Y N Y what is this verify Contents 1 History 2 Mechanism of action 3 Clinical trials 4 Resistance 5 Side effects of pleconaril 6 ReferencesHistory EditPleconaril was originally developed by Sanofi Aventis and licensed to ViroPharma in 1997 ViroPharma developed it further and submitted a New Drug Application to the United States Food and Drug Administration FDA in 2001 The application was rejected citing safety concerns and ViroPharma re licensed it to Schering Plough in 2003 The Phase II clinical trial was completed in 2007 2 A pleconaril intranasal spray had reached phase II clinical trial for the treatment of the common cold symptoms and asthma complications However the results have yet to be reported 6 Mechanism of action EditIn enteroviruses Pleconaril prevents the virus from exposing its RNA and in rhinoviruses Pleconaril prevents the virus from attaching itself to the host cell 7 Human rhinoviruses HRVs contain four structural proteins labeled VP1 VP4 Proteins VP1 VP2 and VP3 are eight stranded anti parallel b barrels VP4 is an extended polypeptide chain on the viral capsid inner surface 8 Pleconaril binds to a hydrophobic pocket in the VP1 protein Pleconaril has been shown in viral assembly to associate with viral particles 9 Through noncovalent hydrophobic interactions compounds can bind to the hydrophobic pocket 10 Amino acids in positions Tyr152 and Val191 are a part of the VP1 drug binding pocket 8 This Image was created in JMOL showing the beta sheets and alpha helices of the Human Rhinovirus The molecule embedded in the hydrophobic pocket of the VP1 protein is Pleconaril In Coxsackievirus Pleconaril efficiency correlates to the susceptibility of CVB3 with the amino acid at position 1092 in the hydrophobic pocket 11 Amino acid 1092 is in close proximity to the central ring of capsid binders 12 The binding of pleconaril in the hydrophobic pocket creates conformational changes which increases the rigidity of the virion and decreases the virions ability to interact with its receptor 13 Drugs bind with the methylisoxazole ring close to the entrance pocket in VP1 the 3 fluromethyl oxadiazole ring at the end of the pocket and the phenyl ring in the center of the pocket 6 Clinical trials EditThe results of two randomized double blind placebo studies found Pleconaril treatment could benefit patients with colds due to picornaviruses 14 Participants in the studies were healthy adults from Canada and the United States with self diagnosed colds that had occurred within 24 hours of trial enrollment Participants were randomly given a placebo or two 200 mg tablets to take three times daily for five days To increase absorption it was recommended to be taken after a meal 14 To monitor the effectiveness of Pleconaril participants recorded the severity of their symptoms and nasal mucosal samples were obtained at enrollment day 3 day 6 and day 18 The two studies had a total of 2096 participants and more than 90 1945 completed the trial The most common reason for a participant not finishing the trial was an adverse event Pleconaril treatment showed a reduction in nose blowing sleep disturbance and less cold medication used 14 Another study showed over 87 of virus isolates in cell culture were inhibited by pleconaril 9 Virus variants were detected in 0 7 of the placebo group and 10 7 of the pleconaril group Of the two isolates a subject from the placebo group had a resistant virus in cell culture to pleconaril The other strain was susceptible to the drug The pleconaril group had 21 virus strains which remained susceptible Resistance strains were found in 7 pleconaril patients 9 A Phase II study that used an intranasal formulation of pleconaril failed to show a statistically significant result for either of its two primary efficacy endpoints percentage of participants with rhinovirus PCR positive colds and percentage of participants with asthma exacerbations together with rhinovirus positive PCR 15 Resistance EditIn human rhinoviruses mutations in amino acids at positions 152 and 191 decrease the efficiency of pleconaril The resistant HRV have phenylalanine at position 152 and leucine at position 191 In vitro studies have shown resistance to pleconaril may emerge The wild type resistance frequency to pleconaril was about 5 10 5 Coxsackievirus B3 CVB3 strain Nancy and other mutants carry amino acid substitutions at position 1092 of Ile1092 gt Leu1092 or Ile1092 gt Met in VP1 The Ile gt Leu mutation causes complete resistance to pleconaril The study found resistance of CVB3 to pleconaril can be overcome by substitution of the central phenyl group Methyl and bromine substitutions created an increase of pleconaril activity towards sensitive and resistant strains Amino acid substitutions in the hydrophobic pocket and receptor binding region of viral capsid proteins were shown to have an effect against the sensitivity of capsid binding antivirals 6 Side effects of pleconaril EditThe U S Food and Drug Administration rejected pleconaril in 2002 due to the side effects The most commonly reported side effects were mild to moderate headache diarrhea and nausea 14 Some women were having symptoms of spotting in between periods Menstrual irregularities were reported by 3 5 of the 320 pleconaril treated women using oral contraceptives and by none of the 291 placebo treated women 14 In the clinical trial two women became pregnant due to the drug interfering with hormonal birth control by activation of cytochrome P 450 3A enzymes Other patients have described painful nasal inflammation 16 References Edit Pharma News Latest Pharma amp Pharmaceutical news amp updates a b Effects of Pleconaril Nasal Spray on Common Cold Symptoms and Asthma Exacerbations Following Rhinovirus Exposure Study P04295AM2 ClinicalTrials gov U S National Institutes of Health March 2007 Retrieved 2007 04 10 Pevear D Tull T Seipel M Groarke J 1999 Activity of pleconaril against enteroviruses Antimicrob Agents Chemother 43 9 2109 15 doi 10 1128 AAC 43 9 2109 PMC 89431 PMID 10471549 Ronald B Turner J Owen Hendley 2005 Virucidal hand treatments for prevention of rhinovirus infection J Antimicrob Chemother 56 5 805 807 doi 10 1093 jac dki329 PMID 16159927 Liu Y et al 2015 Structure and inhibition of EV D68 a virus that causes respiratory illness in children Science 347 6217 71 74 Bibcode 2015Sci 347 71L doi 10 1126 science 1261962 PMC 4307789 PMID 25554786 a b c Schmidtke Michaela Wutzler Peter Zieger Romy Riabova Olga B Makarov Vadim A 2009 New pleconaril and biphenyloxy propyl isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against pleconaril resistant coxsackievirus B3 Antiviral Research 81 1 56 63 doi 10 1016 J ANTIVIRAL 2008 09 002 PMID 18840470 Florea N Maglio D Nicolau D 2003 Pleconaril a novel antipicornaviral agent Pharmacotherapy 23 3 339 48 doi 10 1592 phco 23 3 339 32099 PMC 7168037 PMID 12627933 Free full text with registration a b Ledford Rebecca M Collett Marc S Pevear Daniel C 1 December 2005 Insights into the genetic basis for natural phenotypic resistance of human rhinoviruses to pleconaril Antiviral Research 68 3 135 138 doi 10 1016 j antiviral 2005 08 003 PMID 16199099 a b c Pevear D C Hayden F G Demenczuk T M Barone L R McKinlay M A Collett M S 26 October 2005 Relationship of Pleconaril Susceptibility and Clinical Outcomes in Treatment of Common Colds Caused by Rhinoviruses Antimicrobial Agents and Chemotherapy 49 11 4492 4499 doi 10 1128 AAC 49 11 4492 4499 2005 PMC 1280128 PMID 16251287 Rotbart HA February 2002 Treatment of picornavirus infections Antiviral Research 53 2 83 98 doi 10 1016 s0166 3542 01 00206 6 PMID 11750935 Braun Heike Makarov Vadim A Riabova Olga B Wutzler Peter Schmidtke Michaela 2011 Amino Acid Substitutions At Residue 207 of Viral Capsid Protein 1 VP1 Confer Pleconaril Resistance in Coxsackievirus B3 CVB3 Antiviral Research 90 2 A54 A55 doi 10 1016 j antiviral 2011 03 100 Schmidtke Michaela Wutzler Peter Zieger Romy Riabova Olga B Makarov Vadim A 2009 New pleconaril and biphenyloxy propyl isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against pleconaril resistant coxsackievirus B3 Antiviral Research 81 1 56 63 doi 10 1016 j antiviral 2008 09 002 PMID 18840470 Thibaut Hendrik Jan De Palma Armando M Neyts Johan 2012 Combating enterovirus replication State of the art on antiviral research Biochemical Pharmacology 83 2 185 192 doi 10 1016 j bcp 2011 08 016 PMID 21889497 a b c d e Hayden F G Herrington D T Coats T L Kim K Cooper E C Villano S A Liu S Hudson S Pevear D C Collett M McKinlay M Jun 15 2003 Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults results of 2 double blind randomized placebo controlled trials Pleconaril Respiratory Infection Study Group Clinical Infectious Diseases 36 12 1523 32 doi 10 1086 375069 PMC 7199898 PMID 12802751 National Institutes of Health Effects of Pleconaril Nasal Spray on Common Cold Symptoms and Asthma Exacerbations Following Rhinovirus Exposure Study P04295AM2 Clinical Trials gov Available at http www clinicaltrials gov ct gui show NCT00394914 Accessed July 20 2015 Greenwood Veronique 2011 Curing the Common Cold Scientific American 304 1 30 1 Bibcode 2011SciAm 304a 30G doi 10 1038 scientificamerican0111 30 PMID 21265321 Retrieved 2013 03 25 Retrieved from https en wikipedia org w index php title Pleconaril amp oldid 1123483586, wikipedia, wiki, book, books, library,
