ライフサイエンスコーパス: NS5A

1 HCV proteins, including core, E2, NS4B, and NS5A.

2 of patients had detectable baseline RASs in NS5A.

3 potent antiviral drugs that are targeted to NS5A.

4 ption alters the subcellular distribution of NS5A.

5 between the globular and disordered parts of NS5A.

6 with an altered subcellular distribution of NS5A.

7 be partially transcomplemented by wild-type NS5A.

8 ation of a replication-defective mutation in NS5A.

9 nction and found that MOBKL1B interacts with NS5A.

10 nted by cyclosporine resistance mutations in NS5A.

11 erstanding of the function and regulation of NS5A.

12 without altering HCV RNA colocalization with NS5A.

13 1 (NAP1L1) as an interaction partner of HCV NS5A.

14 tance-associated substitutions in NS3 and/or NS5A.

15 N2034D, E2238G, V2252A, L2266P, and I2340T [NS5A]; A2500S and V2841A [NS5B]), displayed fitness comp

16 ors (39%) than mice that did not express HCV NS5A after the HCFD (6%); only 9% of Tlr4-/- NS5A Tg mic

17 Furthermore, expression of NS5A alone from an additional cistron within a replicon

18 the hepatitis C virus nonstructural protein NS5A, anchored at the cytoplasmic leaflet of the endopla

19 nal switch between the dimeric structures of NS5A and could also explain the different functions of t

20 cted with HCV encoded non-structural protein NS5A and could strongly induce its degradation dependent

21 ar target of the viral nonstructural protein NS5A and demonstrated its role in antiviral signaling.

22 the 7 clinically relevant inhibitors of HCV NS5A and identified variants associated with resistance

23 ther detailed structure/function analysis of NS5A and M3R performed by the ISM method extended with o

24 Our results help to define the function of NS5A and may contribute to an understanding of the mode

25 A daclatasvir derivative interacted with NS5A and molecular docking studies revealed a plausible

26 tures and study the effects of inhibitors of NS5A and NS5B and resistance to sofosbuvir-the only nucl

27 ange that stabilized the interaction between NS5A and TBC1D20, which is required for HCV replication.

28 itis C virus (HCV) nonstructural protein 5A (NS5A) and effects on the viral life cycle.

29 racts with the HCV nonstructural 5A protein (NS5A) and enriches the HCV replication complex with its

30 itis C virus (HCV) nonstructural protein 5A (NS5A) and its interaction with the human chaperone cyclo

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

32 nd/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples col

33 Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at in

34 We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe wit

35 RAVs in NS3, NS5A, and NS5B were detected by population-based sequenc

36 oteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting

37 the N terminus of CIDEB and the domain I of NS5A are involved in this interaction.

38 otein kinases, we identified CKI-alpha as an NS5A-associated kinase involved in NS5A hyperphosphoryla

39 novel mechanistic insights into the roles of NS5A-associated kinases and NS5A phosphorylation in the

40 HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the effic

41 orylation of the viral nonstructural protein NS5A at serine residues is important for the efficient a

42 otein, and this correlated with detection of NS5A at sites where replication occurred.

43 ts who had failed to achieve SVR on previous NS5A-based therapy with daclatasvir (DCV) plus pegylated

44 core MOBKL1B-NS5A peptide complex at 1.95 A, NS5A binds to a hydrophobic patch on the MOBKL1B surface

45 The N-terminal amphipathic helix of NS5A bound specifically to PI(4,5)P2, inducing a conform

46 ll effect on the subcellular distribution of NS5A, but completely prevented biogenesis of the membran

47 yclophilin inhibitor that indirectly targets NS5A by blocking NS5A/cyclophilin A interaction.

48 the effects of PI(4,5)P2 on the function of NS5A by expressing wild-type or mutant forms of Bart79I

49 each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitte

50 pre-existing RAS T/Y93H acquired additional NS5A changes during escape experiments, resulting in HCV

51 Ser-235 phosphorylated NS5A co-localized with double-stranded RNA, consistent w

52 NS5A comprises an N-terminal folded domain, followed by

53 tor that indirectly targets NS5A by blocking NS5A/cyclophilin A interaction.

54 y a short structural motif in the disordered NS5A-D2 and report its NMR structure.

55 is strongly impaired in the binding of both NS5A-D2 and RNA.

56 Thus, our work highlights NS5A-D2 as an allosteric regulator of the HCV polymerase

57 NS5A-D2 induces conformational and functional perturbati

58 The addition of NS5A-D2 leads to spectral changes indicative of binding

59 f NS5B in solution and its relationship with NS5A-D2 remains incomplete.

60 e intrinsically disordered domain 2 of NS5A (NS5A-D2), another essential multifunctional HCV protein

61 ns isomerase activity on residue Pro(314) of NS5A-D2.

62 sed of only the C-terminal residues 191-447 (NS5A-D2D3) allowed us to conclude that there is no signi

63 NS5A-D2D3, despite its overall high flexibility, shows a

64 ons from a culture-efficient JFH1-based core-NS5A (DBN) recombinant, was transfected into Huh7.5 cell

65 ensive domain mapping analyses revealed that NS5A degradation was mediated by the highly conserved SP

66 ausible mode by which the inhibitor bound to NS5A dimers.

67 ion will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resi

68 in MOBKL1B knockdown cells, even though its NS5A does not interact with MOBKL1B.

69 s after viral passage in the NS3 protease or NS5A domain-I regions targeted by the drugs.

70 mbining these two classes acting on distinct NS5A domains represents an attractive strategy for poten

71 We expressed HCV-NS5A from a transgene (NS5A Tg) in Tlr4-/- (C57Bl6/10ScN

72 However, only NS5A from genotype 2 HCV, and not that from genotype 1,

73 could be rescued benefitted from expressing NS5A from the same RNA being packaged.

74 mining the extent to which the two copies of NS5A from the various expression systems colocalize, the

75 ge interactions in nonstructural protein 5A (NS5A) from hepatitis C virus (HCV), a typical viral IDP

76 actors involved in HCV nonstructural protein NS5A function and found that MOBKL1B interacts with NS5A

77 We showed further that the NS5A-GBP1 interaction inhibited GTPase activity, which w

78 Targeting NS5A has become integral in antiviral combinations in cl

79 investigated the role that the viral protein NS5A has in both replication and particle assembly using

80 NS5A has multiple functions during the virus life cycle,

81 Baseline RASs in NS5A have minimal effects on patient responses to ledipa

82 switch to regulate the various functions of NS5A; however, the mechanistic details of the role of th

83 t-derived NS5A sequences by using genotype 4 NS5A hybrid genotype 2a replicons.

84 exity sequence I of NS5A that is involved in NS5A hyperphosphorylation and hyperphosphorylation-depen

85 pha as an NS5A-associated kinase involved in NS5A hyperphosphorylation and the production of infectio

86 mbly than viral replication via mediation of NS5A hyperphosphorylation.

87 I, which is important for CKI-alpha-mediated NS5A hyperphosphorylation.

88 cell environment by targeting NAP1L1 through NS5A.IMPORTANCE Viruses have evolved to replicate and to

89 Mouse hepatocytes that express HCV-NS5A in liver up-regulate the expression of Toll-like re

90 ion therapy and new insight into the role of NS5A in the HCV replication cycle.

91 for phosphorylation at serine 225 (S225) of NS5A in the regulation of JFH-1 (genotype 2a) genome rep

92 HCV dsRNAs (Core, E1-P7, NS-3'NTR and NS5A) induced interferon-lambda1 (IFN-lambda1) expressio

93 asvir targets a mutual, specific function of NS5A inhibiting both processes.

94 The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially

95 Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against c

96 Daclatasvir is an NS5A inhibitor approved for treatment of infection due t

97 f acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step

98 Daclatasvir and ledipasvir belong to the NS5A inhibitor class, which directly target the NS5A pro

99 eatment response with IFNL4 genotype in some NS5A inhibitor containing IFN-free regimens.

100 NS5A inhibitor daclatasvir was exceptionally potent, but

101 iprevir, faldaprevir, and MK-5172 and by the NS5A inhibitor daclatasvir.

102 S3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir together with ribavirin in treat

103 r findings support the concept of retreating NS5A inhibitor failures with SOF combined with SIM.

104 ated with a combination of sofosbuvir and an NS5A inhibitor for 8 weeks.

105 se inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without riba

106 ON program, the single-tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase

107 ed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polyme

108 y and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibi

109 We assessed the efficacy and safety of the NS5A inhibitor ledipasvir and the nucleotide polymerase

110 tide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sust

111 -label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inh

112 f compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater ther

113 itor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside p

114 r ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus t

115 evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavi

116 S3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir for 12 weeks in adults who h

117 of sofosbuvir, given in combination with the NS5A inhibitor velpatasvir and the NS3/4A protease inhib

118 NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfecte

119 tide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose c

120 tide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofo

121 tide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sus

122 leotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhi

123 leotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhi

124 leotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor v

125 erase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir.

126 previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to

127 previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to

128 Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhi

129 BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhi

130 of two direct-acting antivirals, ombitasvir (NS5A inhibitor) and paritaprevir (NS3/4A protease inhibi

131 93 (NS3/4A protease inhibitor) plus ABT-530 (NS5A inhibitor) has shown high rates of sustained virolo

132 e-daily dosage of daclatasvir (pan-genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg

133 tor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and

134 se inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients wi

135 al interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A pr

136 direct-acting antiviral drugs ombitasvir, an NS5A inhibitor, and paritaprevir, an NS3/4A protease inh

137 All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase

138 on of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has sh

139 (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ru

140 (HCV genotypes 1-6) while the indication for NS5A inhibitor- naive patients was limited to HCV genoty

141 nts who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreate

142 ribavirin, in participants who had failed an NS5A inhibitor-containing regimen.

143 with HCV infection who had previously failed NS5A inhibitor-containing therapy.

144 t as to why a broad indication was given for NS5A inhibitor-experienced patients (HCV genotypes 1-6)

145 rapy with an NS3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue.

146 eral blood in a few weeks to months, whereas NS5A inhibitor-resistant viruses persist for years.

147 ergy when combined with interferon or an HCV NS5A inhibitor.

148 r of patients failing regimens containing an NS5A inhibitor.

149 fication of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor.

150 HCV regimen containing sofosbuvir without an NS5A inhibitor.

151 HCV regimen containing sofosbuvir without an NS5A inhibitor.

152 itor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; a

153 /4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (d

154 ing daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes,

155 gimen containing a nonstructural protein 5A (NS5A) inhibitor; and * genotype 1a or 3 infection and ha

156 with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor),

157 ared the efficacy of all clinically relevant NS5A inhibitors against HCV genotype 1-7 prototype isola

158 The presence of viral variants resistant to NS5A inhibitors at baseline is associated with lower rat

159 NS5A inhibitors did not affect NS5A stability or dimeriz

160 ctron microscopy revealed unequivocally that NS5A inhibitors had no overall effect on the subcellular

161 NS5A inhibitors had varying levels of efficacy against o

162 For the remaining NS5A inhibitors tested, RAS at amino acids 28 and 93 led

163 Cells incubated with NS5A inhibitors were rapidly depleted of intracellular i

164 Despite their high potency, NS5A inhibitors were slow to inhibit viral RNA synthesis

165 class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrr

166 selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatmen

167 in the NS5A region conferring resistance to NS5A inhibitors, such as ledipasvir.

168 n the SAR studies available for the reported NS5A inhibitors.

169 otease inhibitors, polymerase inhibitors, or NS5A inhibitors.

170 l chemical class of potent and selective HCV NS5A inhibitors.

171 who have failed on nonstructural protein 5A (NS5A) inhibitors should be retreated with sofosbuvir (SO

172 pectedly, an HCV variant lacking the MOBKL1B-NS5A interaction could not replicate after cells were tr

173 ree proteomics approach to identify cellular NS5A interaction partners.

174 hes, we found no relationship of the MOBKL1B-NS5A interaction to virus replication.

175 virus replication dependence on the MOBKL1B-NS5A interaction was incorrect.

176 ably promotes HCV replication via increasing NS5A interaction with the 33-kDa vesicle-associated memb

177 replication complex formation via increasing NS5A interaction with the human homologue of the 33-kDa

178 that HCV replication depended on the MOBKL1B-NS5A interaction, we carried out structural and biochemi

179 NS5A is a phosphoprotein, and it has been proposed that

180 Although the phosphorylation status of NS5A is considered to have a significant impact on its f

181 NS5A is known to be phosphorylated by cellular protein k

182 NS5A is required for HCV RNA replication and is involved

183 rugs to counteract the worldwide HCV burden, NS5A is still an enigmatic multifunctional protein poorl

184 The non-structural protein 5A (NS5A) is a hepatitis C virus (HCV) protein indispensable

185 HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several

186 itis C virus (HCV) nonstructural protein 5A (NS5A) is a phosphoprotein that plays key, yet poorly def

187 The viral nonstructural 5A protein (NS5A) is the target for new antiviral drugs.

188 d the level and translation of Netrin-1 in a NS5A-La-related protein 1 (LARP1)-dependent fashion.

189 ion sites (serines 222, 235, and 238) in the NS5A low complexity sequence I region.

190 ariants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy;

191 for compensated genotype 1b HCV if baseline NS5A mutations are absent.

192 tracellular colocalization between core, E2, NS5A, NS4B proteins, and viral RNAs was quantitatively a

193 eplication complex (RC) characterized by HCV NS5A, NS4B, or double-stranded RNA (dsRNA) foci.

194 ith the intrinsically disordered domain 2 of NS5A (NS5A-D2), another essential multifunctional HCV pr

195 ) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs.

196 effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions

197 teraction and mapped it to the C terminus of NS5A of both genotype 1 and 2.

198 ling a segment of the nonstructural protein (NS5A) of the hepatitis C virus.

199 as no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end

200 ased on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious

201 ay be important for some of the functions of NS5A over the course of the HCV life cycle.

202 plication defect that mapped to domain II of NS5A (P315A, L321A).

203 d by a cocrystal structure of a core MOBKL1B-NS5A peptide complex at 1.95 A, NS5A binds to a hydropho

204 Mechanisms regulating NS5A phosphorylation and its exact function in the HCV l

205 g to the host protein Bin1, as well as after NS5A phosphorylation by CK2.

206 nto the roles of NS5A-associated kinases and NS5A phosphorylation in the HCV life cycle.

207 function, the mechanistic details regulating NS5A phosphorylation, as well as its exact roles in the

208 ty sequence I region of NS5A responsible for NS5A phosphorylation; however, the functions of specific

209 Most baseline sequences had >/=1 NS5A polymorphism at residues associated with daclatasvi

210 2 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or

211 HCV database, and susceptibility analyses of NS5A polymorphisms and patient-derived NS5A sequences by

212 ation for HCV genotype 4 subtype prevalence, NS5A polymorphisms at residues associated with daclatasv

213 s with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and

214 ere 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001).

215 patients with HCV genotype 1a infection with NS5A polymorphisms.

216 chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of man

217 abile Zn-site in the hepatitis C virus (HCV) NS5A protein and showed that the antialcoholism drug, di

218 S: Inhibitors of the hepatitis C virus (HCV) NS5A protein are a key component of effective treatment

219 raction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one

220 ssays revealed that GBP1 interacted with the NS5A protein of CSFV, and this interaction was mapped in

221 ve revealed that CH25H can interact with the NS5A protein of HCV and inhibit its dimer formation, whi

222 tein, MOBKL1B, as a binding partner with the NS5A protein of hepatitis C virus (HCV).

223 This analysis revealed that NS5A protein represents the most probable interactor of

224 nst CSFV replication, and the binding of the NS5A protein to GBP1 antagonizes the GTPase activity and

225 mbination with elbasvir, an inhibitor of HCV NS5A protein) showed that positions 56, 156, and 168 in

226 Furthermore, CIDEB interacts with the HCV NS5A protein, and the N terminus of CIDEB and the domain

227 the intrinsically disordered domain 2 of HCV NS5A protein.

228 udy specific binding of PI(4,5)P2 by the HCV NS5A protein.

229 A inhibitor class, which directly target the NS5A protein.

230 on a specific amino acid residue in the HCV NS5A protein.

231 he hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is highly phosphorylated and involved in b

232 ith HCV recombinants expressing genotype 1-7 NS5A proteins with or without RAS.

233 egulated by hepatitis C virus (HCV) core and NS5A proteins, and this negative regulation is apparent

234 eletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/beta-caten

235 .6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without.

236 These same baseline NS5A RASs reduced the percentage of treatment-experience

237 The NS5A RAV Y93H is significantly associated with the prese

238 In contrast, the NS5A RAV Y93H was detected frequently in HCV genotype 1b

239 In addition, IFNL4 SNPs and NS5A RAVs were analyzed including deep sequencing (n = 1

240 Human replication protein A (RPA) and HCV NS5A recruit NS5BDelta21 to the template.

241 luding these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize

242 aled a resistance associated mutation in the NS5A region conferring resistance to NS5A inhibitors, su

243 3 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory

244 asunaprevir (64), marketed as Sunvepra, the NS5A replication complex inhibitor daclatasvir (117), ma

245 f the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provi

246 We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a n

247 el trial of the combination of ombitasvir (a NS5A replication complex inhibitor), paritaprevir, and r

248 NS5A replication complex inhibitors, exemplified by dacl

249 ional change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second i

250 logue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhan

251 , a non-CC IL-28B genotype, and pretreatment NS5A resistance-associated variants.

252 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.

253 Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12.

254 Prior to retreatment, 29 patients (85%) had NS5A-resistant variants.

255 s in the low complexity sequence I region of NS5A responsible for NS5A phosphorylation; however, the

256 We showed that HCV NS5A(S25-C447) and cellular replication protein A (RPA)

257 Both RPA and NS5A(S25-C447), but not NS5A(S25-K215), enabled the NS5B

258 Both RPA and NS5A(S25-C447), but not NS5A(S25-K215), enabled the NS5BDelta21-NS3 helicase com

259 apitulated the perinuclear redistribution of NS5A seen in the S225A mutant.

260 es of NS5A polymorphisms and patient-derived NS5A sequences by using genotype 4 NS5A hybrid genotype

261 erformed phylogenetic analysis of genotype 4 NS5A sequences from 186 clinical trial patients and 43 s

262 ective concentrations for 10 patient-derived NS5A sequences representing diverse phylogenetic cluster

263 lication by directly binding with HCV E1 and NS5A sequences.

264 NS5A sequesters NAP1L1 in the cytoplasm, blocking its nu

265 We concluded that NS5A Ser-235 phosphorylated by CKIalpha probably promote

266 d to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inh

267 NS5A inhibitors did not affect NS5A stability or dimerization.

268 tion of embryonic gene clusters, whereas the NS5A TCR activation induced extended proliferative and m

269 A higher proportion of NS5A Tg mice developed liver tumors (39%) than mice that

270 NS5A after the HCFD (6%); only 9% of Tlr4-/- NS5A Tg mice fed HCFD developed liver tumors.

271 Livers from NS5A Tg mice fed the HCFD had increased levels of TLR4,

272 In TICs from NS5A Tg mice, NANOG and pSTAT3 directly interact to acti

273 We expressed HCV-NS5A from a transgene (NS5A Tg) in Tlr4-/- (C57Bl6/10ScN), and wild-type contro

274 interaction was impaired in mutant forms of NS5A that are resistant to daclatavir, providing a possi

275 RASs in NS5A that increased the half-maximal effective concentra

276 cise molecular function has been ascribed to NS5A that is composed of a highly structured domain 1 (D

277 gion within the low-complexity sequence I of NS5A that is involved in NS5A hyperphosphorylation and h

278 eins and show that they interacted only with NS5A that was phosphorylated on a specific residue.

279 We and others have identified serine 225 in NS5A to be a phosphorylation site, but the function of t

280 hat efficient rescue of replication required NS5A to be expressed as part of a larger polyprotein, an

281 modification is required for the binding of NS5A to other cellular proteins.

282 PI(4,5)P2 binds to HCV NS5A to promote replication of the viral RNA genome in h

283 ficient virus replication and the ability of NS5A to spread throughout the cytoplasm of the cell.

284 HCFD and HCV-NS5A together stimulated TLR4-NANOG and the leptin recep

285 Every NS3 and NS5A variant detected at baseline reappeared at the time

286 eline NS5A polymorphisms and emergent NS3 or NS5A variants or both.

287 atidylinositol 4-phosphate), the mutation in NS5A was restricted to a perinuclear region.

288 Y93H in NS5A was the RAS most frequently associated with failure

289 067R (NS3) had reverted to Q1067 and S2204I (NS5A) was replaced by T2204 within 8 weeks of infection.

290 RAS hotspots in NS5A were found at amino acids 28, 30, 31, and 93.

291 RASs in NS5A were heterogeneous among patients with HCV genotype

292 and a perinuclear restricted distribution of NS5A, whereas the corresponding phosphomimetic mutation

293 ting antiviral agent and potent inhibitor of NS5A, which is involved in replication of the hepatitis

294 ting antiviral agent and potent inhibitor of NS5A, which is involved in replication of the hepatitis

295 infection is the viral nonstructural protein NS5A, which, in addition to its role in replication and

296 hosphorylation regulates the interactions of NS5A with a defined subset of cellular proteins.

297 S225A mutation disrupted the interactions of NS5A with a number of cellular proteins, in particular t

298 Phospho-proteomic analysis of NS5A with or without CKI-alpha depletion identified pept

299 ar magnetic resonance spectra of full-length NS5A with those of a protein construct composed of only

300 nfected with a daclatasvir-resistant mutant (NS5A-Y93H), indicating that daclatasvir targets a mutual