ライフサイエンスコーパス: NS5B

1 ity within the hepatitis C virus polymerase (NS5B).

2 n of the viral RNA-dependent RNA polymerase (NS5B).

3 osine as a potent and selective inhibitor of NS5B.

4 arily conferred by the S282T substitution in NS5B.

5 s is the viral RNA-dependent RNA polymerase, NS5B.

6 patitis C virus (HCV) proteins NS3, NS4, and NS5B.

7 information on QAZ binding interactions with NS5B.

8 rotease and the RNA-dependent RNA polymerase NS5B.

9 ophobic binding pocket at the palm region of NS5B.

10 ted, HCV-796 showed slow binding kinetics to NS5B.

11 include a 1:1 complex formed between NS3 and NS5B.

12 n the helicase, NS3, and the RNA polymerase, NS5B.

13 oduct formation increased in the presence of NS5B.

14 SNPs and rare and common RAVs within NS3 and NS5B.

15 tivity, which is specifically antagonized by NS5B.

16 es 2629 to 2637 of nonstructural protein 5B (NS5B(2629-2637)) (KSKKTPMGF) and E2(541-549) (NTRPPLGNW)

17 the subdominant HLA-B27-restricted epitope, NS5B(2936-2944) (GRAAICGKY), to further define the mecha

18 -NS5A (5-5A) from genotypes 1-6 and 2a(JFH1) NS5B-3' untranslated region, and tested the effects of N

19 5' untranslated region (5'UTR)-NS5A and JFH1 NS5B-3'UTR; recovered viruses acquired two adaptive muta

20 Immunoblot analyses showed that NS5B abundance was not reduced until after 12 h, suggest

21 hat the culture-adaptive mutations in p7 and NS5B acted synergistically to enhance the specific viral

22 ns thus add to the diversifying pool of anti-NS5B agents and provide a novel scaffold for structural

23 mergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced vi

24 We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy.

25 Generic and specific NS5b amplicons were produced by real-time polymease chai

26 HCV nonstructural 5B (NS5B) amplicons (n = 94) were generated from 77 individu

27 t antiviral agent specifically targeting HCV NS5B, an RNA-dependent RNA polymerase.

28 Stau1 coimmunoprecipitates HCV NS5B and a cell factor, protein kinase R (PKR), which is

29 prehensive description of RNA replication by NS5B and is relevant to understanding the functional pro

30 e for the viral RNA-dependent RNA polymerase NS5B and p7 proteins in contributing to virion morphogen

31 study the effects of inhibitors of NS5A and NS5B and resistance to sofosbuvir-the only nucleotide an

32 ably low dissociation rate for wild type HCV NS5B, and a highly dynamic enzyme-RNA binary complex.

33 ts of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs)

34 of viral replicase proteins, including NS5A, NS5B, and NS3.

35 NS3, NS4A, NS4B, NS5A, and NS5B appear to interact structurally and functionally.

36 between the Delta1 loop and thumb domain in NS5B are required for de novo initiation, although it is

37 reveal a genetic interaction between p7 and NS5B, as well as an interaction with sphingomyelin that

38 Activity against NS5B bearing the S282T mutation was reduced.

39 g kinetics profile and only slightly reduced NS5B binding affinity of HCV-796.

40 Co-crystal structures of NS5B-Con1 and NS5B-BK with HCV-796 revealed a deep hydrophobic binding

41 NS5B bound a long, 378-nucleotide HCV RNA oligonucleotid

42 his loss of replication competence, purified NS5B-C316A protein was two- to threefold more active tha

43 associated variants were identified, and the NS5B changes observed did not confer significant reducti

44 A number of treatment-associated NS5B changes were observed and characterized.

45 ssociated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the f

46 cting replication element located within the NS5B coding region of hepatitis C virus (HCV) were deter

47 netically conserved RNA structure within the NS5B coding region of hepatitis C virus functions as a c

48 NA elements and an extended stem-loop in the NS5B coding region.

49 ication element (CRE), is located within the NS5B coding region.

50 Co-crystal structures of NS5B-Con1 and NS5B-BK with HCV-796 revealed a deep hydro

51 with a strain-DBN coding sequence, modified NS5B consensus sequence, pS52 untranslated regions, and

52 ne SA13/JFH1orig mutant termed SA13/JFH1Core-NS5B, containing 13 amino acid changes (R114W and V187A

53 that under optimized conditions up to 65% of NS5B could be converted into active elongation complexes

54 Analyses of these variants modeled in NS5B crystal structures indicated that all four substitu

55 Despite this importance and the existence of NS5B crystal structures, our understanding of the confor

56 he NS3-helicase (F1464L), NS4A (A1672S), and NS5B (D2979G) were adapted and improved, by incorporatin

57 We show that both NS5B(Delta21) and CypA share a common binding site on NS

58 een detected by NMR spectroscopy between HCV NS5B(Delta21) and host CypA.

59 data highlight the potential of using NMR of NS5B(Delta21) as a powerful tool to characterize in solu

60 gh quality heteronuclear NMR spectrum of HCV NS5B(Delta21) has been obtained and was used to characte

61 cyclosporine A added to a sample containing NS5B(Delta21), NS5A-D2, and CypA specifically inhibits t

62 on B), and 306-333 (region C)) interact with NS5B(Delta21), whereas NS5A-D3 does not.

63 without altering the one between NS5A-D2 and NS5B(Delta21).

64 d 3 of NS5A (NS5A-D2 and NS5A-D3), CypA, and NS5B(Delta21).

65 2266P, and I2340T [NS5A]; A2500S and V2841A [NS5B]), displayed fitness comparable to that of the poly

66 virals targeting the HCV protease, NS5A, and NS5B, each inhibited full-length TN infection dose-depen

67 9) as a potent inhibitor of RNA synthesis by NS5B (EC(50) = 1.28 microM), the RNA polymerase encoded

68 d 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 muM) and cell-based replicon

69 NS5B-expression also results in liver damage.

70 ulture-efficient DBN-based recombinants with NS5B from HCV genotype 3a strains S52 and DH11.

71 NS5B from the cyclosporine-resistant replicon was resist

72 The RNA polymerase (gene product NS5B) from the hepatitis C virus is responsible for repl

73 le the C-terminus plays a regulatory role in NS5B function.

74 ial natural drug-resistance mutations in the NS5B gene of HCV genotype 1b from treatment-naive patien

75 is associated with distinct mutations in the NS5B gene that increase RNA binding in the presence of C

76 -based sequencing and 454 deep sequencing of NS5B gene were performed on plasma and liver samples obt

77 2 patients, consistent with their genotype 1 NS5B gene.

78 sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at

79 Binding studies with NS5B genetic variants (WT, L30S, and P495L) exposed a tw

80 NS5B has a structure resembling an open right hand (cont

81 The Y448H mutation in NS5B has been selected by GS-9190 as well as several ben

82 ucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durab

83 Our studies also demonstrate that NS5B HCV RNA polymerase was able to accommodate 2',4'-di

84 The formation of the NS5B-HCV RNA complex did not affect the slow binding kin

85 ch site alters the structure and dynamics of NS5B in a distinct manner.

86 in was two- to threefold more active than wt NS5B in cell-free polymerase and replicase assays.

87 el role for the RNA-dependent RNA polymerase NS5B in HCV assembly.

88 f the conformational and dynamic behavior of NS5B in solution and its relationship with NS5A-D2 remai

89 nd provides new insight into the dynamics of NS5B in solution.

90 of HCV RNA-dependent RNA polymerase (RdRp), NS5B, in mouse liver and human hepatocytes results in pr

91 n of an escape variant with substitutions in NS5B, including the resistance-associated substitution S

92 The binding affinity of HCV-796 to NS5B increased 27-fold over a 3-h incubation period with

93 itory beta-hairpin loop from genotype 2a HCV NS5B increases de novo RNA synthesis by >100-fold, promo

94 to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral a

95 atitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients

96 inhibitor vedroprevir (VDV), non-nucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in t

97 Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral

98 (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in geno

99 groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genot

100 nation with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks

101 rs should be retreated with sofosbuvir (SOF; NS5B inhibitor) combined with simeprevir (SIM; protease

102 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazo

103 nhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3.

104 inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection.

105 se inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluate

106 re reported with an allosteric nonnucleoside NS5B inhibitor.

107 e to characterize mechanism of inhibition of NS5B inhibitors against either template RNA poly(A) or p

108 ently, and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development.

109 ort the identification of a new class of HCV NS5B inhibitors belonging to the coumestan family of phy

110 y of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced.

111 the identification of new chemotypes of HCV NS5B inhibitors.

112 ort the discovery of a C-nucleoside class of NS5B inhibitors.

113 uctural refinement and development of potent NS5B inhibitors.

114 d fitness and with cross-resistance to other NS5B inhibitors.

115 containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described.

116 NS5B interacts with the intrinsically disordered domain

117 nt specifically blocked the incorporation of NS5B into the RC without affecting either the total prot

118 s key functional role during the life cycle, NS5B intrapatient variability was low.

119 teraction with the induced binding pocket on NS5B is consistent with slow binding kinetics and loss o

120 NS5B is the RNA-dependent RNA polymerase responsible for

121 ase from the Hepatitis C Virus (gene product NS5B) is a validated drug target because of its critical

122 tis C virus (HCV) non-structural protein 5B (NS5B) is an RNA-dependent RNA polymerase that is essenti

123 Nonstructural protein 5B (NS5B) is essential for hepatitis C virus (HCV) replicati

124 Non-structural protein 5B (NS5B) is the RNA-dependent RNA polymerase that catalyzes

125 ct monitoring of the interaction between HCV NS5B, its RNA template, and finger loop inhibitors.

126 y escape mutations within the immunodominant NS5B KSKKTPMGF epitope may contribute in part to the con

127 c T lymphocyte (CTL) escape mutations in the NS5B KSKKTPMGF epitope might impair viral replication an

128 irst detailed NMR spectroscopic study of HCV NS5B lacking its membrane anchor (NS5BDelta21).

129 The HCV RNA abundance and NS5B levels are significantly reduced by the small inter

130 his compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown

131 Mutant NS5B made by cells expressing the HCV replicon had incre

132 Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and ma

133 ear whether these interactions are within an NS5B monomer or are part of a higher-order NS5B oligomer

134 Additional identified NS4B and NS5B mutations fully adapted the TN full-length virus.

135 h the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with g

136 ibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with

137 n with genetic vaccines encoding the HCV NS3-NS5b nonstructural proteins during DAA treatment resulte

138 hepatitis C viral genome is catalyzed by the NS5B (nonstructural protein 5B) RNA-dependent RNA polyme

139 Moreover, differences between NS5B nonsynonymous (dN) and synonymous (dS) mutation rat

140 rehension of the molecular interplay between NS5B, NS5A, and CypA, three essentials proteins for HCV

141 quent high-resolution mutational analysis of NS5B (nt 7787 to 9289) using approximately 51-nucleotide

142 next-generation NS3 protease inhibitors, and NS5B nucleoside and nonnucleoside inhibitors, has provid

143 3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue.

144 NS5B nucleotide diversity continued to increase for at l

145 Overall, 2.5% of patients had baseline NS5B nucleotide inhibitor RASs (L159F, N142T, S282G, or

146 regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was show

147 is C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and

148 mographic data was created by sequencing the NS5B of 125 genotype 1a (Gt1a) samples and 166 Gt3a samp

149 n NS5B monomer or are part of a higher-order NS5B oligomeric complex.

150 presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants),

151 nd structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughpu

152 or a representative derivative was mapped to NS5B palm site I employing a mutant counterscreen assay,

153 We used BLAST analyses of NS5B partial sequences to establish the genotype and sub

154 related well with resistance -fold shifts in NS5B polymerase activity and replicon assays.

155 Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms

156 d inhibition of: HCV cell culture infection, NS5B polymerase activity, TNF-alpha-induced NF-kappaB tr

157 We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination par

158 series, exhibiting a IC50 of 7.9 muM against NS5B polymerase and antiviral effect (EC50 = 8.1 muM; EC

159 leosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in

160 xhibiting an IC50 value of 0.069 muM against NS5B polymerase and selective antiviral effect (EC50 = 3

161 Moreover, we demonstrated that the HCV NS5B polymerase associates with CypA via its enzymatic p

162 Pure compounds inhibited JFH-1 NS5B polymerase but only at concentrations above 300 muM

163 longation complex of the medically important NS5B polymerase for structural and functional studies.

164 The HCV NS5B polymerase has been demonstrated to be a viable tar

165 Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relation

166 BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A ant

167 7), marketed as Daklinza, and the allosteric NS5B polymerase inhibitor beclabuvir (142), which is in

168 bitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in li

169 HCV NS5B polymerase inhibitor GSK852A (1) was synthesized in

170 Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferre

171 We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibi

172 y with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HC

173 bitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) +/- ribavirin for 12 or 24 we

174 ) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV

175 /r), in addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatm

176 5A inhibitor, ledipasvir, combined with the NS5B polymerase inhibitor, sofosbuvir, in patients with

177 0 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day).

178 hange conferring resistance to nucleos(t)ide NS5B polymerase inhibitors and in 16 patients the C316N/

179 stance to SOF and other nucleos(t)ide analog NS5B polymerase inhibitors are not well understood.

180 acid series of allosteric thumb pocket 2 HCV NS5B polymerase inhibitors exhibited hindered rotation a

181 ants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas va

182 se inhibitor class and other classes such as NS5B polymerase inhibitors, NS5A inhibitors and cyclophi

183 s of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors.

184 antivirals (DAAs), such as NS3 protease and NS5B polymerase inhibitors.

185 The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and h

186 The NS5B polymerase may be inhibited directly through the ac

187 ect-acting antiviral (DAA) targeting the HCV NS5b polymerase protein.

188 V polymerase NS5B to wild-type and resistant NS5B polymerase proteins was determined, and the influen

189 omer of a compound bound to the intended HCV NS5B polymerase target whereas the mirror image atropiso

190 iophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site.

191 b pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon sys

192 triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polym

193 ic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of

194 ng chemotype against hepatitis C virus (HCV) NS5B polymerase, a validated and promising anti-HCV targ

195 uinolone derivatives as potent inhibitors of NS5B polymerase, an attractive and viable therapeutic ta

196 hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targe

197 ree viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A.

198 conformation of the NS3-4A protease and the NS5B polymerase, membrane-bound HCV replicase components

199 t intrinsic biochemical activity against the NS5B polymerase, with IC50 = 8.48 muM.

200 rated that HCV NS3/NS4A protease-, NS5A- and NS5B polymerase-directed drugs respectively inhibited fu

201 op inhibitors of the hepatitis C virus (HCV) NS5B polymerase.

202 ctivity against both wild-type and S282T HCV NS5B polymerase.

203 lective inhibitor of hepatitis C virus (HCV) NS5B polymerase.

204 e NS3/4A protease, the NS5A protein, and the NS5B polymerase.

205 btaining novel anti-HCV agents targeting the NS5B polymerase.

206 nd by reagents that inhibit NS3 protease and NS5B polymerase.

207 30), a potent and selective inhibitor of HCV NS5B polymerase.

208 phosphate (8), a potent inhibitor of the HCV NS5B polymerase.

209 ing nucleoside triphosphates against the HCV NS5B polymerase.

210 de of work, the formation of a highly active NS5B polymerase.RNA complex suitable for mechanistic and

211 itis C virus (HCV) nonstructural protein 5B (NS5B) polymerase and inhibits viral replication.

212 arly active against both wild-type and S282T NS5B polymerases.

213 C virus (HCV) requires proteins from the NS3-NS5B polyprotein to create a replicase unit for replicat

214 hat highly conserved active-site residues in NS5B position the primer for in-line attack on the incom

215 tions, we were able to generate a productive NS5B.primer.template elongation complex stalled after fo

216 Original NS5b probes were designed for genotypes 1a/1b, 2a/2b/2c,

217 In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-al

218 ythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently rep

219 periments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amio

220 er experiments revealed that the HCV NS2 and NS5B proteins are responsible for the HCV-associated dec

221 Purified recombinant NS5B proteins containing the mutations were better at de

222 Here, we demonstrate that the viral p7 and NS5B proteins cooperate to promote virion infectivity by

223 The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets afte

224 of reduction of NNI binding affinity for the NS5B proteins with various resistance mutations in the p

225 es revealed the localization of HCV NS5A and NS5B proteins, which are two important components of the

226 pitopes in the E2, nonstructural (NS)5a, and NS5b proteins.

227 Sequencing of the NS5B region identified a number of amino acid changes, i

228 the 5' UTR in all eight subjects and for the NS5B region in five subjects.

229 acted from serum samples, and the 5' UTR and NS5B region were sequenced.

230 and is based on the sequencing of the viral NS5b region.

231 uggesting CRE structures are enriched in the NS5B region.

232 Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial rela

233 The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of

234 The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhi

235 gue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with

236 s, including the NS3/4A serine protease, the NS5B RNA polymerase, NS5A, and NS4B.

237 arin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at con

238 C viral (HCV) genome is accomplished by the NS5B RNA-dependent RNA polymerase (RdRp), for which mech

239 ugs which are known as inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp).

240 Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class

241 as an alternative substrate inhibitor of the NS5B RNA-dependent RNA polymerase during HCV replication

242 ne ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying

243 hese include new NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors, NS5A inhib

244 The NS5B RNA-dependent RNA polymerase is an attractive targe

245 To inhibit the HCV NS5B RNA-dependent RNA polymerase, PSI-7851 must be meta

246 ations, identified in the p7 polypeptide and NS5B RNA-dependent RNA polymerase, were sufficient to in

247 log inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across

248 chanism for formation of a productive binary NS5B-RNA complex, here NS5B slides along the RNA templat

249 dies revealed important properties of static NS5B-RNA complexes, the nature and relevance of dynamic

250 dex score of 3 or 4) and 1 with a detectable NS5B S282T mutation after sofosbuvir plus ribavirin ther

251 bitor PSI-6130) is rare and conferred by the NS5B S282T mutation.

252 ntration and population sequencing to detect NS5B S282T mutations.

253 The NS5B S282T resistance mutation was not observed in any p

254 No evidence of NS5B S282T-variant virus or phenotypic resistance to mer

255 NS5B sequence diversity assessed by deep sequencing can

256 was infected with HCV that had more than 95% NS5B sequence homology with the HCV strains of the 3 cas

257 -third that of virus with the wild-type (wt) NS5B sequence.

258 Partial E1 and/or NS5B sequences from 411 volunteer blood donors sampled i

259 We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA fail

260 No viral resistance was observed, per NS5B sequencing and phenotypic studies.

261 NS5B sequencing and susceptibility testing of HCV from s

262 nformational and functional perturbations in NS5B similar to those triggered by filibuvir.

263 stigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell c

264 f a productive binary NS5B-RNA complex, here NS5B slides along the RNA template facilitating position

265 a high barrier to resistance, with no S282T NS5B substitution or phenotypic resistance detected in p

266 arrier to resistance; however, low-frequency NS5B substitutions associated with treatment failure wer

267 The NS5B substitutions, L159F (sometimes in combination with

268 Additionally, mutations in C, E1, NS3, and NS5B synergistically promoted HCV production in the back

269 CV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs.

270 y of further investigation in the context of NS5B-targeted HCV drug discovery programs.

271 reveal a genetic interaction between p7 and NS5B that contributes to virion specific infectivity.

272 ions revealed a fully closed conformation of NS5B that may facilitate de novo initiation of RNA repli

273 identified three mutations in NS3, NS4A, and NS5B that permitted full-length J6 propagation and adapt

274 ue to mutations in nonstructural protein 5B (NS5B), the HCV-encoded polymerase.

275 e an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase.

276 ion may also be pertinent to designing novel NS5B therapeutics.

277 ation of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied

278 of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently repor

279 to result from the inability of the mutated NS5B to optimally regulate Rb abundance and thereby modu

280 HCV uses NS5B to specifically suppress NORE1A, facilitating viral

281 to monitor temporal changes upon binding of NS5B to surface immobilized RNA templates.

282 cleoside inhibitors (NNIs) of HCV polymerase NS5B to wild-type and resistant NS5B polymerase proteins

283 Here, emergence of the NS5B variants L159F and V321A and possible association w

284 Deep-sequencing analysis confirmed that NS5B variants L159F and V321A emerged in a subset of pat

285 No NS5B variants present at baseline among 1645 sofosbuvir-

286 performed molecular dynamics simulations of NS5B variants with different C-terminal lengths in the p

287 cell-to-cell transmission for SA13/JFH1Core-NS5B viruses as well as viruses with only p7 and nonstru

288 oding non-structural proteins NS4B, NS5A and NS5B, we assessed the ability of peripheral immunization

289 us reports of very low proportions of active NS5B, we observed that under optimized conditions up to

290 RAVs in NS3, NS5A, and NS5B were detected by population-based sequencing.

291 NS5A and NS5B were partially sequenced, and mutation rates were c

292 taining mutations in the Rb-binding motif of NS5B which ablate the ability of HCV to regulate Rb.

293 cells via an interaction with RC-associated NS5B, which is sensitive to cyclosporine treatment.

294 side and nucleotide analogs that inhibit HCV NS5B, which led to the FDA approval of sofosbuvir in 201

295 HCV-796 was driven by slow dissociation from NS5B with a k(off) of 4.9 +/- 0.5 x 10(-4) s(-1).

296 on of association-dissociation events of HCV-NS5B with RNA, and also the direct monitoring of the int

297 hepatitis C virus genes (E1, E2, NS2, NS4B, NS5B), with an emphasis on including as many sequences w

298 strated that SA13/JFH1orig and SA13/JFH1Core-NS5B, with and without the E2 mutation T385P, displayed

299 tations in core (C), E1, NS2, NS3, NS5A, and NS5B, with the majority of mutations clustered in NS5A.

300 ected, all patient samples were wild type at NS5B Y448 by population sequencing.