viral nonstructural proteins


Summary: Proteins encoded by a VIRAL GENOME that are produced in the organisms they infect, but not packaged into the VIRUS PARTICLES. Some of these proteins may play roles within the infected cell during VIRUS REPLICATION or act in regulation of virus replication or VIRUS ASSEMBLY.

Top Publications

  1. Kowdley K, Lawitz E, Poordad F, Cohen D, Nelson D, Zeuzem S, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014;370:222-32 pubmed publisher
  2. Manfroni G, Cannalire R, Barreca M, Kaushik Basu N, Leyssen P, Winquist J, et al. The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors. J Med Chem. 2014;57:1952-63 pubmed publisher
    ..These results indicate that the 6-aminoquinolone scaffold is worthy of further investigation in the context of NS5B-targeted HCV drug discovery programs. ..
  3. Yu L, Takeda K, Markoff L. Protein-protein interactions among West Nile non-structural proteins and transmembrane complex formation in mammalian cells. Virology. 2013;446:365-77 pubmed publisher
    ..NS2B protein seems to play a key role in bringing the TPs together on the ER membrane and in bridging the TPs with non-membrane-associated proteins (NS3 and NS5). ..
  4. Guo H, Sun X, Yan L, Shao L, Fang Q. The NS16 protein of aquareovirus-C is a fusion-associated small transmembrane (FAST) protein, and its activity can be enhanced by the nonstructural protein NS26. Virus Res. 2013;171:129-37 pubmed publisher
    ..Our study provided a basis for further characterization of cell-cell fusion mediated by AqRV-C. ..
  5. Pawlotsky J. NS5A inhibitors in the treatment of hepatitis C. J Hepatol. 2013;59:375-82 pubmed publisher
    ..Clinical trials using combination therapies containing NS5A inhibitors have reported results that promise high cure rates and raise the possibility of developing interferon-free, all-oral regimens. ..
  6. Ross Thriepland D, Amako Y, Harris M. The C terminus of NS5A domain II is a key determinant of hepatitis C virus genome replication, but is not required for virion assembly and release. J Gen Virol. 2013;94:1009-18 pubmed publisher
    ..Comparison of our data with a previously published analysis of the same region in genotype 1b revealed some important differences between the two genotypes of HCV...
  7. Nichols D, Leão R, Basu A, Chudayeu M, de Moraes P, Talele T, et al. Evaluation of coumarin and neoflavone derivatives as HCV NS5B polymerase inhibitors. Chem Biol Drug Des. 2013;81:607-14 pubmed publisher
    ..NS5B-TP-1-8a interaction map provided insight into 8a binding and offered clues for future SAR optimization...
  8. Fridell R, Valera L, Qiu D, Kirk M, Wang C, Gao M. Intragenic complementation of hepatitis C virus NS5A RNA replication-defective alleles. J Virol. 2013;87:2320-9 pubmed publisher
    ..We postulate that these complementation groups define three distinct and genetically separable functions of NS5A in RNA replication. ..
  9. Bartels D, Sullivan J, Zhang E, Tigges A, Dorrian J, De Meyer S, et al. Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment. J Virol. 2013;87:1544-53 pubmed publisher
    ..The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied. ..

More Information


  1. Meng J, Zhang Z, Zheng Z, Liu Y, Wang H. Methionine-101 from one strain of H5N1 NS1 protein determines its IFN-antagonizing ability and subcellular distribution pattern. Sci China Life Sci. 2012;55:933-9 pubmed publisher
    ..In addition, methionine-101 was the key residue for the NS1-CPSF30 interaction. This study reveals the importance of methionine-101 in the influenza A virus life cycle and may provide valuable information for antiviral strategies. ..
  2. Lim P, Chatterji U, Cordek D, Sharma S, Garcia Rivera J, Cameron C, et al. Correlation between NS5A dimerization and hepatitis C virus replication. J Biol Chem. 2012;287:30861-73 pubmed publisher
    ..Altogether our data suggest that NS5A-NS5A dimerization and/or multimerization could represent a novel target for the development of HCV therapies. ..
  3. Melik W, Ellencrona K, Wigerius M, Hedström C, Elväng A, Johansson M. Two PDZ binding motifs within NS5 have roles in Tick-borne encephalitis virus replication. Virus Res. 2012;169:54-62 pubmed publisher
    ..A different pattern was observed for WNVNS5 as it associate with a broader repertoire of putative host PDZ proteins. ..
  4. Jagger B, Wise H, Kash J, Walters K, Wills N, Xiao Y, et al. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science. 2012;337:199-204 pubmed publisher
    ..Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis. ..
  5. Lihoradova O, Kalveram B, Indran S, Lokugamage N, Juelich T, Hill T, et al. The dominant-negative inhibition of double-stranded RNA-dependent protein kinase PKR increases the efficacy of Rift Valley fever virus MP-12 vaccine. J Virol. 2012;86:7650-61 pubmed publisher
  6. Maroniche G, Mongelli V, Llauger G, Alfonso V, Taboga O, del Vas M. In vivo subcellular localization of Mal de Río Cuarto virus (MRCV) non-structural proteins in insect cells reveals their putative functions. Virology. 2012;430:81-9 pubmed publisher
    ..Finally, P9-2 was N-glycosylated and located at the plasma membrane in association with filopodia-like protrusions containing actin, suggesting a possible role in virus cell-to-cell movement and spread. ..
  7. Kumar A, Bühler S, Selisko B, Davidson A, Mulder K, Canard B, et al. Nuclear localization of dengue virus nonstructural protein 5 does not strictly correlate with efficient viral RNA replication and inhibition of type I interferon signaling. J Virol. 2013;87:4545-57 pubmed publisher
    ..These results indicate that efficient DENV RNA replication requires only minimal, if any, nuclear NS5, and they identify the ??NLS as a structural element required for proper RdRp activity. ..
  8. Sun Z, Zhang S, Xie L, Zhu Q, Tan Z, Bian J, et al. The secretory pathway and the actomyosin motility system are required for plasmodesmatal localization of the P7-1 of rice black-streaked dwarf virus. Arch Virol. 2013;158:1055-64 pubmed publisher
    ..The plasmodesmatal localization of RBSDV P7-1 is therefore dependent on the secretory pathway and the actomyosin motility system...
  9. Muller D, Young P. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res. 2013;98:192-208 pubmed publisher
    ..In this article, we provide an overview of these somewhat disparate areas of research, drawing together the wealth of data generated over more than 40 years of study of this fascinating protein. ..
  10. Leger P, Lara E, Jagla B, Sismeiro O, Mansuroglu Z, Coppee J, et al. Dicer-2- and Piwi-mediated RNA interference in Rift Valley fever virus-infected mosquito cells. J Virol. 2013;87:1631-48 pubmed publisher
    ..This study provides new insights into the role of Dicer and Piwi in mosquito antiviral defense and the development of the antiviral response in mosquitoes. ..
  11. Paolucci S, Fiorina L, Piralla A, Gulminetti R, Novati S, Barbarini G, et al. Naturally occurring mutations to HCV protease inhibitors in treatment-naïve patients. Virol J. 2012;9:245 pubmed publisher
    ..A more extensive analysis is needed to better evaluate the impact of baseline resistance and compensatory mutations in the efficacy of HCV PI treatment. ..
  12. Saalau Bethell S, Woodhead A, Chessari G, Carr M, Coyle J, Graham B, et al. Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function. Nat Chem Biol. 2012;8:920-5 pubmed publisher
    ..We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents. ..
  13. Liu Y, Huang P, Tan M, Liu Y, Biesiada J, Meller J, et al. Rotavirus VP8*: phylogeny, host range, and interaction with histo-blood group antigens. J Virol. 2012;86:9899-910 pubmed publisher
    ..Our study suggests that HBGAs play an important role in RV infection and evolution. ..
  14. Yu G, He G, Li C, Tang M, Grivennikov S, Tsai W, et al. Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production. Mol Cell. 2012;48:313-21 pubmed publisher
    ..NS5B-expression also results in liver damage. ..
  15. Varshney J, Sharma P, Sharma A. A review on an update of NS5B polymerase hepatitis C virus inhibitors. Eur Rev Med Pharmacol Sci. 2012;16:667-71 pubmed
    ..These demanding efforts have resulted in various promising agents advancing in clinical development with emphasis on clinical efficacy and impact for future combination studies. ..
  16. Gentile I, Borgia F, Buonomo A, Castaldo G, Borgia G. A novel promising therapeutic option against hepatitis C virus: an oral nucleotide NS5B polymerase inhibitor sofosbuvir. Curr Med Chem. 2013;20:3733-42 pubmed
    ..Safety and tolerability of sofosbuvir appear to be excellent. In conclusion, sofosbuvir especially in interferon-free combinations represents a very promising option in the treatment of chronic hepatitis C. ..
  17. Xie X, Gayen S, Kang C, Yuan Z, Shi P. Membrane topology and function of dengue virus NS2A protein. J Virol. 2013;87:4609-22 pubmed publisher
    ..The topology model of DENV NS2A provides a good starting point for studying how flavivirus NS2A modulates viral replication and evasion of host immune response. ..
  18. Melian E, Edmonds J, Nagasaki T, Hinzman E, Floden N, Khromykh A. West Nile virus NS2A protein facilitates virus-induced apoptosis independently of interferon response. J Gen Virol. 2013;94:308-13 pubmed publisher
  19. Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E. RNA 3'-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proc Natl Acad Sci U S A. 2012;109:9372-7 pubmed publisher
    ..In addition to the activation of nsp16-mediated 2'-O-MTase activity, nsp10 also activates nsp14 in an RNA processing function potentially connected to a replicative mismatch repair mechanism. ..
  20. Hu L, Chow D, Patton J, Palzkill T, Estes M, Prasad B. Crystallographic Analysis of Rotavirus NSP2-RNA Complex Reveals Specific Recognition of 5' GG Sequence for RTPase Activity. J Virol. 2012;86:10547-57 pubmed publisher
  21. Poordad F, Lawitz E, Kowdley K, Cohen D, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013;368:45-53 pubmed publisher
    ..Funded by Abbott; number, NCT01306617.). ..
  22. Kim Y, Gayen S, Kang C, Joy J, Huang Q, Chen A, et al. NMR analysis of a novel enzymatically active unlinked dengue NS2B-NS3 protease complex. J Biol Chem. 2013;288:12891-900 pubmed publisher
    ..This protease complex can serve as a useful tool for drug discovery against DENV. ..
  23. Alves R, Queiroz A, Pessoa M, da Silva E, Mazo D, Carrilho F, et al. The presence of resistance mutations to protease and polymerase inhibitors in Hepatitis C virus sequences from the Los Alamos databank. J Viral Hepat. 2013;20:414-21 pubmed publisher
    ..Likewise, genotype 1b isolates and genotype 1a sequences exhibited pre-existing mutations associated with resistance to Palm II and Thumb I polymerase inhibitors, respectively...
  24. Stern O, Hung Y, Valdau O, Yaffe Y, Harris E, Hoffmann S, et al. An N-terminal amphipathic helix in dengue virus nonstructural protein 4A mediates oligomerization and is essential for replication. J Virol. 2013;87:4080-5 pubmed publisher
    ..These data emphasize the significance of NS4A in the life cycle of the dengue virus and demarcate it as a target for the design of novel antiviral therapy...
  25. Andries A, Duong V, Ngan C, Ong S, Huy R, Sroin K, et al. Field evaluation and impact on clinical management of a rapid diagnostic kit that detects dengue NS1, IgM and IgG. PLoS Negl Trop Dis. 2012;6:e1993 pubmed publisher
  26. Mänz B, Brunotte L, Reuther P, Schwemmle M. Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells. Nat Commun. 2012;3:802 pubmed publisher
    ..In conclusion, when crossing the species barrier, avian influenza viruses acquire adaptive mutations in nuclear export protein to escape restricted viral genome replication in mammalian cells. ..
  27. Palanisamy N, Danielsson A, Kokkula C, Yin H, Bondeson K, Wesslén L, et al. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res. 2013;99:12-7 pubmed publisher
    ..Moreover, the natural polymorphisms in genotype 2b (i.e. S122R) and 3a (i.e. D168Q), with inherent PI drug resistance of up to 20 and 700 fold respectively, would explain why current PIs are primarily directed against genotype 1...
  28. Lemay K, Treadaway J, Angulo I, Tellinghuisen T. A hepatitis C virus NS5A phosphorylation site that regulates RNA replication. J Virol. 2013;87:1255-60 pubmed publisher
    ..This site is a component of the hyperphosphorylated form of NS5A, which is in good agreement with previous observations that hyperphosphorylation negatively affects replication. ..
  29. Lu G, Gong P. Crystal Structure of the full-length Japanese encephalitis virus NS5 reveals a conserved methyltransferase-polymerase interface. PLoS Pathog. 2013;9:e1003549 pubmed publisher
    ..Our work paves the way for further dissection of the inter-regulations of the essential enzymatic activities of NS5 and exploration of possible other conformations of NS5 under different circumstances. ..
  30. Gori Savellini G, Valentini M, Cusi M. Toscana virus NSs protein inhibits the induction of type I interferon by interacting with RIG-I. J Virol. 2013;87:6660-7 pubmed publisher
    ..These results contribute to identify a novel mechanism for bunyaviruses by which TOSV NSs counteracts the early IFN response. ..
  31. Youn S, Li T, McCune B, Edeling M, Fremont D, Cristea I, et al. Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus. J Virol. 2012;86:7360-71 pubmed publisher
    ..Mass spectrometry and coimmunoprecipitation studies established a novel physical interaction between NS1 and NS4B, suggesting a mechanism for how luminal NS1 conveys signals to the cytoplasm to regulate RNA replication. ..
  32. Tan C, Hobson Peters J, Stoermer M, Fairlie D, Khromykh A, Hall R. An interaction between the methyltransferase and RNA dependent RNA polymerase domains of the West Nile virus NS5 protein. J Gen Virol. 2013;94:1961-71 pubmed publisher
  33. Bartenschlager R, Lohmann V, Penin F. The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat Rev Microbiol. 2013;11:482-96 pubmed publisher
  34. Feuerstein S, Solyom Z, Aladag A, Favier A, Schwarten M, Hoffmann S, et al. Transient structure and SH3 interaction sites in an intrinsically disordered fragment of the hepatitis C virus protein NS5A. J Mol Biol. 2012;420:310-23 pubmed publisher
    ..The present work also highlights the power of NMR spectroscopy to characterize multiple binding events including short-lived transient interactions between globular and highly disordered proteins. ..
  35. Gayen S, Chen A, Huang Q, Kang C. West Nile Virus (WNV) protease and membrane interactions revealed by NMR spectroscopy. Biochem Biophys Res Commun. 2012;423:799-804 pubmed publisher
    ..This region may serve as an anchoring site to stabilized NS3 protease domain on the membrane. ..
  36. Suzuki F, Sezaki H, Akuta N, Suzuki Y, Seko Y, Kawamura Y, et al. Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b. J Clin Virol. 2012;54:352-4 pubmed publisher
    ..Since single mutations did not result in treatment failure in a previous pilot trial combining BMS-790052 and an NS3 inhibitor, larger trials of this drug regimen appear warranted in the Japanese population. ..
  37. Fros J, Domeradzka N, Baggen J, Geertsema C, Flipse J, Vlak J, et al. Chikungunya virus nsP3 blocks stress granule assembly by recruitment of G3BP into cytoplasmic foci. J Virol. 2012;86:10873-9 pubmed publisher
    ..A conserved SH3 domain-binding motif in nsP3 is essential for both nsP3-G3BP interactions and viral RNA replication. This study reveals a novel role for nsP3 as a regulator of the cellular stress response...
  38. Lu H, Xu X, Gao N, Fan D, Wang J, An J. Preliminary evaluation of DNA vaccine candidates encoding dengue-2 prM/E and NS1: their immunity and protective efficacy in mice. Mol Immunol. 2013;54:109-14 pubmed publisher
    ..Our data suggested that pCAG-DG offered better protection against DENV2 infection. ..
  39. Morrison J, Aguirre S, Fernandez Sesma A. Innate immunity evasion by Dengue virus. Viruses. 2012;4:397-413 pubmed publisher
    ..In this review, we will evaluate the contribution of innate immunity evasion by DENV to the pathogenesis and host tropism of this virus. ..
  40. Ploen D, Hafirassou M, Himmelsbach K, Sauter D, Biniossek M, Weiss T, et al. TIP47 plays a crucial role in the life cycle of hepatitis C virus. J Hepatol. 2013;58:1081-8 pubmed publisher
    ..Complete knockdown of TIP47 expression abolishes virus replication. TIP47 plays an essential role in the HCV life cycle. ..
  41. Kalveram B, Lihoradova O, Indran S, Lokugamage N, Head J, Ikegami T. Rift Valley fever virus NSs inhibits host transcription independently of the degradation of dsRNA-dependent protein kinase PKR. Virology. 2013;435:415-24 pubmed publisher
  42. Rajsbaum R, Albrecht R, Wang M, Maharaj N, Versteeg G, Nistal Villán E, et al. Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein. PLoS Pathog. 2012;8:e1003059 pubmed publisher
    ..In conclusion, our results indicate that influenza NS1 protein targets TRIM25 and Riplet ubiquitin E3 ligases in a species-specific manner for the inhibition of RIG-I ubiquitination and antiviral IFN production...
  43. Norris C, He K, Springer M, Hartnett K, Horn J, Aizenman E. Regulation of neuronal proapoptotic potassium currents by the hepatitis C virus nonstructural protein 5A. J Neurosci. 2012;32:8865-70 pubmed publisher
    ..1. Our results indicate that NS5A1b limits K+ currents following injury, leading to increased neuronal viability. NS5A1b may thus serve as a model for a new generation of neuroprotective agents. ..
  44. Benferhat R, Josse T, Albaud B, Gentien D, Mansuroglu Z, Marcato V, et al. Large-scale chromatin immunoprecipitation with promoter sequence microarray analysis of the interaction of the NSs protein of Rift Valley fever virus with regulatory DNA regions of the host genome. J Virol. 2012;86:11333-44 pubmed publisher
  45. Young L, Melian E, Khromykh A. NS1' colocalizes with NS1 and can substitute for NS1 in West Nile virus replication. J Virol. 2013;87:9384-90 pubmed publisher
    ..Using complementation analysis with NS1-deleted WNV cDNA, we demonstrated that NS1' is able to substitute for the crucial function of NS1 in virus replication. ..
  46. Lange C, Zeuzem S. Perspectives and challenges of interferon-free therapy for chronic hepatitis C. J Hepatol. 2013;58:583-92 pubmed publisher
    ..In this review, we summarize available data of interferon-free regimens for the treatment of chronic hepatitis C and assess implications for perspectives and challenges in the further development of all-oral therapies. ..
  47. Schaefer E, Chung R. Anti-hepatitis C virus drugs in development. Gastroenterology. 2012;142:1340-1350.e1 pubmed publisher
    ..These new reagents against hepatitis C virus should lead to highly effective, well-tolerated, and likely interferon-sparing therapies in the next several years. ..
  48. Gebhard L, Kaufman S, Gamarnik A. Novel ATP-independent RNA annealing activity of the dengue virus NS3 helicase. PLoS ONE. 2012;7:e36244 pubmed publisher
    ..We propose that, according to the ATP availability, NS3 could function regulating the folding or unfolding of viral RNA structures. ..
  49. Gane E, Stedman C, Hyland R, Ding X, Svarovskaia E, Symonds W, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34-44 pubmed publisher
    ..Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection. (Funded by Pharmasset and Gilead Sciences; number, NCT01260350.). ..
  50. Guedj J, Dahari H, Rong L, Sansone N, Nettles R, Cotler S, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci U S A. 2013;110:3991-6 pubmed publisher
    ..The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV...
  51. Austin D, Baer A, Lundberg L, Shafagati N, Schoonmaker A, Narayanan A, et al. p53 Activation following Rift Valley fever virus infection contributes to cell death and viral production. PLoS ONE. 2012;7:e36327 pubmed publisher
    ..Collectively, these experiments indicate that the p53 signaling pathway is utilized during RVFV infection to induce cell death and increase viral production. ..
  52. de la Cruz Hernández S, Flores Aguilar H, González Mateos S, Lopez Martinez I, Alpuche Aranda C, Ludert J, et al. Determination of viremia and concentration of circulating nonstructural protein 1 in patients infected with dengue virus in Mexico. Am J Trop Med Hyg. 2013;88:446-54 pubmed publisher
    ..0001). Results indicate that levels of circulating NS1 vary according to the infecting serotype, immunologic status (primary or secondary infection), and dengue disease severity...
  53. Salam K, Furuta A, Noda N, Tsuneda S, Sekiguchi Y, Yamashita A, et al. Psammaplin A inhibits hepatitis C virus NS3 helicase. J Nat Med. 2013;67:765-72 pubmed publisher
    ..1 and 6.3 ?M in subgenomic replicon cells derived from genotypes 1b and 2a, respectively. We postulate that psammaplin A is a potential anti-viral agent through the inhibition of ATPase, RNA binding and helicase activities of NS3...