Selection and Characterization of Replicon Variants Dually Resistant to Thumb- and Palm-Binding Nonnucleoside Polymerase Inhibitors of the Hepatitis C Virus

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Published inJournal of Virology Vol. 80; no. 12; pp. 6146 - 6154
Main Authors Le Pogam, Sophie, Kang, Hyunsoon, Harris, Seth F., Leveque, Vincent, Giannetti, Anthony M., Ali, Samir, Jiang, Wen-Rong, Rajyaguru, Sonal, Tavares, Gisele, Oshiro, Connie, Hendricks, Than, Klumpp, Klaus, Symons, Julian, Browner, Michelle F., Cammack, Nick, Nájera, Isabel
Format Journal Article
LanguageEnglish
Published Washington, DC American Society for Microbiology 01.06.2006
Subjects
Antiviral Agents - pharmacology
Biological and medical sciences
Carboxylic Acids
Drug Resistance, Viral
Drug Therapy, Combination
Fundamental and applied biological sciences. Psychology
Genetic Variation
Hepacivirus - drug effects
Hepacivirus - enzymology
Hepacivirus - genetics
Hepatitis C virus
Microbiology
Miscellaneous
Mutation, Missense
Replicon - genetics
RNA-Dependent RNA Polymerase - antagonists & inhibitors
Selection, Genetic
Thiophenes - pharmacology
Vaccines and Antiviral Agents
Viral Nonstructural Proteins - antagonists & inhibitors
Virology
Virus Replication
Virus
Resistance
Microbiology
Flaviviridae
Hepatitis C virus
Hepacivirus
Virology
Online AccessGet full text
ISSN0022-538X
1098-5514
DOI10.1128/JVI.02628-05

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Abstract Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue JVI About JVI Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy JVI RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0022-538X Online ISSN: 1098-5514 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to JVI .asm.org, visit: JVI       
AbstractList Multiple nonnucleoside inhibitor binding sites have been identified within the hepatitis C virus (HCV) polymerase, including in the palm and thumb domains. After a single treatment with a thumb site inhibitor (thiophene-2-carboxylic acid NNI-1), resistant HCV replicon variants emerged that contained mutations at residues Leu419, Met423, and Ile482 in the polymerase thumb domain. Binding studies using wild-type (WT) and mutant enzymes and structure-based modeling showed that the mechanism of resistance is through the reduced binding of the inhibitor to the mutant enzymes. Combined treatment with a thumb- and a palm-binding polymerase inhibitor had a dramatic impact on the number of replicon colonies able to replicate in the presence of both inhibitors. A more exact characterization through molecular cloning showed that 97.7% of replicons contained amino acid substitutions that conferred resistance to either of the inhibitors. Of those, 65% contained simultaneously multiple amino acid substitutions that conferred resistance to both inhibitors. Double-mutant replicons Met414Leu and Met423Thr were predominantly selected, which showed reduced replication capacity compared to the WT replicon. These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme. Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple-resistant mutants.
Multiple nonnucleoside inhibitor binding sites have been identified within the hepatitis C virus (HCV) polymerase, including in the palm and thumb domains. After a single treatment with a thumb site inhibitor (thiophene-2-carboxylic acid NNI-1), resistant HCV replicon variants emerged that contained mutations at residues Leu419, Met423, and Ile482 in the polymerase thumb domain. Binding studies using wild-type (WT) and mutant enzymes and structure-based modeling showed that the mechanism of resistance is through the reduced binding of the inhibitor to the mutant enzymes. Combined treatment with a thumb- and a palm-binding polymerase inhibitor had a dramatic impact on the number of replicon colonies able to replicate in the presence of both inhibitors. A more exact characterization through molecular cloning showed that 97.7% of replicons contained amino acid substitutions that conferred resistance to either of the inhibitors. Of those, 65% contained simultaneously multiple amino acid substitutions that conferred resistance to both inhibitors. Double-mutant replicons Met414Leu and Met423Thr were predominantly selected, which showed reduced replication capacity compared to the WT replicon. These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme. Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple-resistant mutants.Multiple nonnucleoside inhibitor binding sites have been identified within the hepatitis C virus (HCV) polymerase, including in the palm and thumb domains. After a single treatment with a thumb site inhibitor (thiophene-2-carboxylic acid NNI-1), resistant HCV replicon variants emerged that contained mutations at residues Leu419, Met423, and Ile482 in the polymerase thumb domain. Binding studies using wild-type (WT) and mutant enzymes and structure-based modeling showed that the mechanism of resistance is through the reduced binding of the inhibitor to the mutant enzymes. Combined treatment with a thumb- and a palm-binding polymerase inhibitor had a dramatic impact on the number of replicon colonies able to replicate in the presence of both inhibitors. A more exact characterization through molecular cloning showed that 97.7% of replicons contained amino acid substitutions that conferred resistance to either of the inhibitors. Of those, 65% contained simultaneously multiple amino acid substitutions that conferred resistance to both inhibitors. Double-mutant replicons Met414Leu and Met423Thr were predominantly selected, which showed reduced replication capacity compared to the WT replicon. These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme. Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple-resistant mutants.
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Author Than Hendricks
Nick Cammack
Vincent Leveque
Isabel Nájera
Samir Ali
Anthony M. Giannetti
Seth F. Harris
Klaus Klumpp
Wen-Rong Jiang
Michelle F. Browner
Connie Oshiro
Gisele Tavares
Sonal Rajyaguru
Sophie Le Pogam
Julian Symons
Hyunsoon Kang
AuthorAffiliation Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304
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Cites_doi 10.1093/jac/dkh319
10.1128/AAC.47.11.3525-3530.2003
10.1016/S0140-6736(01)06102-5
10.1128/JVI.77.5.3007-3019.2003
10.1016/j.bmcl.2003.10.068
10.1073/pnas.0400660101
10.1586/14737159.6.2.207
10.1074/jbc.M505423200
10.1107/S0907444996012255
10.1021/jm050855s
10.1074/jbc.M510195200
10.1038/361186a0
10.1074/jbc.M205566200
10.1055/s-2000-9506
10.1074/jbc.M506407200
10.1074/jbc.M209397200
10.1128/JVI.77.13.7575-7581.2003
10.1128/JVI.77.24.13225-13231.2003
10.1038/35073673
10.1128/JVI.78.2.938-946.2004
10.1016/j.bmcl.2003.10.023
10.1074/jbc.M413410200
10.1099/vir.0.80401-0
10.1038/13305
10.1016/j.bmcl.2003.10.067
10.1016/S0076-6879(97)76066-X
10.1056/NEJMoa020047
10.1099/vir.0.80500-0
10.1016/j.virol.2004.11.024
10.1074/jbc.M109261200
10.1016/S0969-2126(97)00261-X
10.1016/j.bmcl.2003.12.032
10.1107/S0907444905001617
10.1128/JVI.77.6.3669-3679.2003
10.1021/jm040134d
10.1107/S0907444904019158
10.1128/AAC.49.10.4305-4314.2005
10.1128/JVI.75.10.4614-4624.2001
10.1016/0378-1119(85)90017-4
10.1128/JVI.79.7.4340-4346.2005
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Keywords Virus
Resistance
Microbiology
Flaviviridae
Hepatitis C virus
Hepacivirus
Virology
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Corresponding author. Mailing address: Department of HCV Biology, Viral Diseases Therapeutic Area, Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304. Phone: (650) 855-5134. Fax: (650) 354-7554. E-mail: isabel.najera@roche.com.
Present address: Novartis Institutes for Biomedical Research, Basel, Switzerland.
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References e_1_3_2_26_2
e_1_3_2_27_2
e_1_3_2_28_2
e_1_3_2_29_2
e_1_3_2_41_2
e_1_3_2_40_2
e_1_3_2_20_2
e_1_3_2_43_2
e_1_3_2_21_2
e_1_3_2_42_2
e_1_3_2_22_2
e_1_3_2_45_2
e_1_3_2_23_2
e_1_3_2_44_2
e_1_3_2_24_2
e_1_3_2_25_2
e_1_3_2_15_2
e_1_3_2_38_2
e_1_3_2_8_2
e_1_3_2_16_2
e_1_3_2_37_2
e_1_3_2_7_2
e_1_3_2_17_2
e_1_3_2_6_2
e_1_3_2_18_2
e_1_3_2_39_2
e_1_3_2_19_2
(e_1_3_2_9_2) 1994; 50
e_1_3_2_30_2
e_1_3_2_32_2
e_1_3_2_10_2
e_1_3_2_31_2
e_1_3_2_5_2
e_1_3_2_11_2
e_1_3_2_34_2
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References_xml – ident: e_1_3_2_38_2
  doi: 10.1093/jac/dkh319
– ident: e_1_3_2_34_2
  doi: 10.1128/AAC.47.11.3525-3530.2003
– ident: e_1_3_2_28_2
  doi: 10.1016/S0140-6736(01)06102-5
– ident: e_1_3_2_24_2
  doi: 10.1128/JVI.77.5.3007-3019.2003
– ident: e_1_3_2_7_2
  doi: 10.1016/j.bmcl.2003.10.068
– ident: e_1_3_2_8_2
  doi: 10.1073/pnas.0400660101
– ident: e_1_3_2_10_2
  doi: 10.1586/14737159.6.2.207
– ident: e_1_3_2_13_2
  doi: 10.1074/jbc.M505423200
– ident: e_1_3_2_32_2
  doi: 10.1107/S0907444996012255
– ident: e_1_3_2_40_2
  doi: 10.1021/jm050855s
– ident: e_1_3_2_19_2
  doi: 10.1074/jbc.M510195200
– ident: e_1_3_2_27_2
  doi: 10.1038/361186a0
– ident: e_1_3_2_12_2
  doi: 10.1074/jbc.M205566200
– ident: e_1_3_2_45_2
  doi: 10.1055/s-2000-9506
– ident: e_1_3_2_21_2
  doi: 10.1074/jbc.M506407200
– ident: e_1_3_2_44_2
  doi: 10.1074/jbc.M209397200
– ident: e_1_3_2_25_2
  doi: 10.1128/JVI.77.13.7575-7581.2003
– ident: e_1_3_2_41_2
  doi: 10.1128/JVI.77.24.13225-13231.2003
– ident: e_1_3_2_36_2
  doi: 10.1038/35073673
– ident: e_1_3_2_42_2
  doi: 10.1128/JVI.78.2.938-946.2004
– ident: e_1_3_2_3_2
  doi: 10.1016/j.bmcl.2003.10.023
– ident: e_1_3_2_11_2
– ident: e_1_3_2_5_2
  doi: 10.1074/jbc.M413410200
– ident: e_1_3_2_37_2
– ident: e_1_3_2_39_2
  doi: 10.1099/vir.0.80401-0
– ident: e_1_3_2_22_2
– ident: e_1_3_2_23_2
  doi: 10.1038/13305
– ident: e_1_3_2_6_2
  doi: 10.1016/j.bmcl.2003.10.067
– ident: e_1_3_2_35_2
  doi: 10.1016/S0076-6879(97)76066-X
– ident: e_1_3_2_16_2
  doi: 10.1056/NEJMoa020047
– ident: e_1_3_2_29_2
  doi: 10.1099/vir.0.80500-0
– ident: e_1_3_2_26_2
  doi: 10.1016/j.virol.2004.11.024
– ident: e_1_3_2_33_2
  doi: 10.1074/jbc.M109261200
– volume: 50
  start-page: 760
  year: 1994
  ident: e_1_3_2_9_2
  publication-title: Acta Cryst.
– ident: e_1_3_2_17_2
  doi: 10.1016/S0969-2126(97)00261-X
– ident: e_1_3_2_2_2
  doi: 10.1016/j.bmcl.2003.12.032
– ident: e_1_3_2_30_2
  doi: 10.1107/S0907444905001617
– ident: e_1_3_2_43_2
  doi: 10.1128/JVI.77.6.3669-3679.2003
– ident: e_1_3_2_4_2
  doi: 10.1021/jm040134d
– ident: e_1_3_2_15_2
  doi: 10.1107/S0907444904019158
– ident: e_1_3_2_31_2
  doi: 10.1128/AAC.49.10.4305-4314.2005
– ident: e_1_3_2_20_2
  doi: 10.1128/JVI.75.10.4614-4624.2001
– ident: e_1_3_2_14_2
  doi: 10.1016/0378-1119(85)90017-4
– ident: e_1_3_2_18_2
  doi: 10.1128/JVI.79.7.4340-4346.2005
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Multiple nonnucleoside inhibitor binding sites have been identified within the hepatitis C virus (HCV) polymerase, including in the palm and thumb domains....
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SubjectTerms Antiviral Agents - pharmacology
Biological and medical sciences
Carboxylic Acids
Drug Resistance, Viral
Drug Therapy, Combination
Fundamental and applied biological sciences. Psychology
Genetic Variation
Hepacivirus - drug effects
Hepacivirus - enzymology
Hepacivirus - genetics
Hepatitis C virus
Microbiology
Miscellaneous
Mutation, Missense
Replicon - genetics
RNA-Dependent RNA Polymerase - antagonists & inhibitors
Selection, Genetic
Thiophenes - pharmacology
Vaccines and Antiviral Agents
Viral Nonstructural Proteins - antagonists & inhibitors
Virology
Virus Replication
Title Selection and Characterization of Replicon Variants Dually Resistant to Thumb- and Palm-Binding Nonnucleoside Polymerase Inhibitors of the Hepatitis C Virus
URI http://jvi.asm.org/content/80/12/6146.abstract
https://www.ncbi.nlm.nih.gov/pubmed/16731953
https://www.proquest.com/docview/17238778
https://www.proquest.com/docview/68019563
https://pubmed.ncbi.nlm.nih.gov/PMC1472602
Volume 80
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