Viral and cellular RNA helicases as antiviral targets

Although there has been considerable progress in the development of antiviral agents in recent years, there is still a pressing need for new drugs both to improve on the properties of existing agents and to combat the problem of viral resistance. Helicases, both viral and human, have recently emerged as novel targets for the treatment of viral infections. Here, we discuss the role of these enzymes, factors affecting their potential as drug targets and progress in the development of agents that inhibit their activity using the hepatitis C virus-encoded helicase NS3 and the cellular helicase DDX3 adopted for use by HIV-1 as examples.

[1]  J. Walker,et al.  Distantly related sequences in the alpha‐ and beta‐subunits of ATP synthase, myosin, kinases and other ATP‐requiring enzymes and a common nucleotide binding fold. , 1982, The EMBO journal.

[2]  R K Craig,et al.  Methods in molecular medicine. , 1987, British medical journal.

[3]  P. Slonimski,et al.  Birth of the D-E-A-D box , 1989, Nature.

[4]  I. Lehman,et al.  Herpes simplex virus 1 helicase-primase: a complex of three herpes-encoded gene products. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Eugene V. Koonin,et al.  Helicases: amino acid sequence comparisons and structure-function relationships , 1993 .

[6]  E. Koonin,et al.  Evolution and taxonomy of positive-strand RNA viruses: implications of comparative analysis of amino acid sequences. , 1993, Critical reviews in biochemistry and molecular biology.

[7]  O. Jolobe Angiotensin-converting enzyme inhibitors. , 1995, British journal of hospital medicine.

[8]  I. Lehman,et al.  Inhibition of herpes simplex virus type 1 helicase-primase by (dichloroanilino)purines and -pyrimidines. , 1995, Journal of medicinal chemistry.

[9]  K. Bjornson,et al.  Mechanisms of helicase-catalyzed DNA unwinding. , 1996, Annual review of biochemistry.

[10]  L. Bird,et al.  Crystal structure of a DExx box DNA helicase , 1996, Nature.

[11]  G. Seelig,et al.  Enzymatic characterization of hepatitis C virus NS3/4A complexes expressed in mammalian cells by using the herpes simplex virus amplicon system , 1996, Journal of virology.

[12]  M. Murcko,et al.  Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4A Cofactor Peptide , 1996, Cell.

[13]  D. Richman The implications of drug resistance for strategies of combination antiviral chemotherapy. , 1996, Antiviral research.

[14]  Marco M. Kessler,et al.  Hrp1, a sequence-specific RNA-binding protein that shuttles between the nucleus and the cytoplasm, is required for mRNA 3'-end formation in yeast. , 1997, Genes & development.

[15]  C. Lin,et al.  Polynucleotide modulation of the protease, nucleoside triphosphatase, and helicase activities of a hepatitis C virus NS3-NS4A complex isolated from transfected COS cells , 1997, Journal of virology.

[16]  G. Kadaré,et al.  Virus-encoded RNA helicases , 1997, Journal of virology.

[17]  A. Kwong,et al.  Structure of the hepatitis C virus RNA helicase domain , 1997, Nature Structural Biology.

[18]  M. Fournier,et al.  The rRNA-processing function of the yeast U14 small nucleolar RNA can be rescued by a conserved RNA helicase-like protein , 1997, Molecular and cellular biology.

[19]  J. Choe,et al.  Mutational analysis of the hepatitis C virus RNA helicase , 1997, Journal of virology.

[20]  U. Stahl,et al.  The protein family of RNA helicases. , 1998, Critical reviews in biochemistry and molecular biology.

[21]  M. G. Peterson,et al.  Inhibition of Herpes Simplex Virus Replication by a 2-Amino Thiazole via Interactions with the Helicase Component of the UL5-UL8-UL52 Complex , 1998, Journal of Virology.

[22]  P. Weber,et al.  Helicase, a target for novel inhibitors of hepatitis C virus. , 1998, Antiviral therapy.

[23]  David J. T. Porter Inhibition of the Hepatitis C Virus Helicase-associated ATPase Activity by the Combination of ADP, NaF, MgCl2, and Poly(rU) , 1998, The Journal of Biological Chemistry.

[24]  Yan Liu,et al.  Dbp5p, a cytosolic RNA helicase, is required for poly(A)+ RNA export , 1998, The EMBO journal.

[25]  J P Griffith,et al.  Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. , 1998, Structure.

[26]  M. Hanlon,et al.  Product Release Is the Major Contributor tok cat for the Hepatitis C Virus Helicase-catalyzed Strand Separation of Short Duplex DNA* , 1998, The Journal of Biological Chemistry.

[27]  David J. T. Porter A Kinetic Analysis of the Oligonucleotide-modulated ATPase Activity of the Helicase Domain of the NS3 Protein from Hepatitis C Virus , 1998, The Journal of Biological Chemistry.

[28]  P. Linder,et al.  Dbp7p, a putative ATP-dependent RNA helicase from Saccharomyces cerevisiae, is required for 60S ribosomal subunit assembly. , 1998, RNA.

[29]  P. Weber,et al.  Construction, expression, and characterization of a novel fully activated recombinant single‐chain hepatitis C virus protease , 1998, Protein science : a publication of the Protein Society.

[30]  B. Oh,et al.  Crystal Structure of RNA Helicase from Genotype 1b Hepatitis C Virus , 1998, The Journal of Biological Chemistry.

[31]  R. De Francesco,et al.  Multiple Enzymatic Activities Associated with Recombinant NS3 Protein of Hepatitis C Virus , 1998, Journal of Virology.

[32]  P. Jones Strategies for Antiviral Drug Discovery , 1998, Antiviral chemistry & chemotherapy.

[33]  B. Séraphin,et al.  Dbp5, a DEAD‐box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/Nup159p , 1999, The EMBO journal.

[34]  B. Séraphin,et al.  Dbp 5 , a DEAD-box protein required for mRNA export , is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN / Nup 159 p , 1999 .

[35]  Charles A. Lesburg,et al.  Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site , 1999, Nature Structural Biology.

[36]  N. Habuka,et al.  Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. , 1999, Structure.

[37]  Chao Lin,et al.  Structure-Based Mutagenesis Study of Hepatitis C Virus NS3 Helicase , 1999, Journal of Virology.

[38]  J. de la Cruz,et al.  Unwinding RNA in Saccharomyces cerevisiae: DEAD-box proteins and related families. , 1999, Trends in biochemical sciences.

[39]  R. De Francesco,et al.  Modulation of hepatitis C virus NS3 protease and helicase activities through the interaction with NS4A. , 1999, Biochemistry.

[40]  A. Kwong,et al.  Structure and function of hepatitis C virus NS3 helicase. , 2000, Current topics in microbiology and immunology.

[41]  Development of a hepatitis C virus RNA helicase high throughput assay. , 2000, Methods in molecular medicine.

[42]  M. Kalitzky,et al.  ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy. , 2000, Acta biochimica Polonica.

[43]  D. Wigley,et al.  Unwinding the 'Gordian knot' of helicase action. , 2001, Trends in biochemical sciences.

[44]  M. Sim,et al.  Biological evaluation of hepatitis C virus helicase inhibitors. , 2001, Bioorganic & medicinal chemistry letters.

[45]  F. Stutz,et al.  mRNA export: Travelling with DEAD box proteins , 2001, Current Biology.

[46]  S. Weller,et al.  A tale of two HSV-1 helicases: roles of phage and animal virus helicases in DNA replication and recombination. , 2001, Progress in nucleic acid research and molecular biology.

[47]  N. Tanner,et al.  DExD/H box RNA helicases: from generic motors to specific dissociation functions. , 2001, Molecular cell.

[48]  J. Lorsch RNA Chaperones Exist and DEAD Box Proteins Get a Life , 2002, Cell.

[49]  C. Crumpacker,et al.  New anti-HSV therapeutics target the helicase–primase complex , 2002, Nature Medicine.

[50]  H. Schmitz,et al.  Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy. , 2002, Antiviral research.

[51]  D. Mckay,et al.  Helicase structure and mechanism. , 2002, Current opinion in structural biology.

[52]  E. De Clercq,et al.  Strategies in the design of antiviral drugs , 2002, Nature reviews. Drug discovery.

[53]  U. Betz,et al.  Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293 , 2002, Antimicrobial Agents and Chemotherapy.

[54]  F. Rey,et al.  Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides , 2002, Journal of Virology.

[55]  G. Dreyfuss,et al.  Messenger-RNA-binding proteins and the messages they carry , 2002, Nature Reviews Molecular Cell Biology.

[56]  G. Maga,et al.  Hepatitis C virus NS3 ATPase/helicase: an ATP switch regulates the cooperativity among the different substrate binding sites. , 2002, Biochemistry.

[57]  D. Wigley,et al.  Modularity and Specialization in Superfamily 1 and 2 Helicases , 2002, Journal of bacteriology.

[58]  J. Keldenich,et al.  New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease , 2002, Nature Medicine.

[59]  Steven R. LaPlante,et al.  An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus , 2003, Nature.

[60]  Smita S. Patel,et al.  ATP Binding Modulates the Nucleic Acid Affinity of Hepatitis C Virus Helicase* , 2003, Journal of Biological Chemistry.

[61]  Dieter Häussinger,et al.  Abrogation of hepatitis C virus NS3 helicase enzymatic activity by recombinant human antibodies. , 2003, The Journal of general virology.

[62]  M. Minczuk,et al.  Potent inhibition of NTPase/helicase of the West Nile Virus by ring-expanded ("fat") nucleoside analogues. , 2003, Journal of medicinal chemistry.

[63]  A. Lam,et al.  Two novel conserved motifs in the hepatitis C virus NS3 protein critical for helicase action. , 2003, The Journal of biological chemistry.

[64]  P. Bonneau,et al.  An NS 3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus , 2003 .

[65]  D. Wyss,et al.  Double‐stranded DNA‐induced localized unfolding of HCV NS3 helicase subdomain 2 , 2003, Protein science : a publication of the Protein Society.

[66]  A. Lam,et al.  Electrostatic analysis of the hepatitis C virus NS3 helicase reveals both active and allosteric site locations. , 2004, Nucleic acids research.

[67]  L. Strokovskaya,et al.  Direct fluorometric measurement of hepatitis C virus helicase activity , 2004, FEBS letters.

[68]  V. Wilson,et al.  Papillomavirus E1 Proteins: Form, Function, and Features , 2002, Virus Genes.

[69]  V. Serebrov,et al.  Periodic cycles of RNA unwinding and pausing by hepatitis C virus NS3 helicase , 2004, Nature.

[70]  Hui Zhang,et al.  A DEAD box protein facilitates HIV-1 replication as a cellular co-factor of Rev. , 2004, Virology.

[71]  Anton J. Enright,et al.  References and Notes Materials and Methods Som Text Figs. S1 to S9 Tables S1 to S3 References and Notes Protein Displacement by Dexh/d " Rna Helicases " without Duplex Unwinding , 2022 .

[72]  K. Jeang,et al.  Requirement of DDX3 DEAD Box RNA Helicase for HIV-1 Rev-RRE Export Function , 2004, Cell.

[73]  Smita S. Patel,et al.  Helicases as Molecular Motors , 2004 .

[74]  Baohua Gu,et al.  The Nonstructural Protein 3 Protease/Helicase Requires an Intact Protease Domain to Unwind Duplex RNA Efficiently* , 2004, Journal of Biological Chemistry.

[75]  Ding‐Shinn Chen,et al.  Hepatitis C virus NS3 RNA helicase activity is modulated by the two domains of NS3 and NS4A. , 2004, Biochemical and biophysical research communications.

[76]  P. Linder,et al.  DEAD-box proteins: the driving forces behind RNA metabolism , 2004, Nature Reviews Molecular Cell Biology.

[77]  Kyungsook Han,et al.  Isolation of specific and high-affinity RNA aptamers against NS3 helicase domain of hepatitis C virus. , 2004, RNA.

[78]  F. Penin,et al.  Membrane Association of the RNA-Dependent RNA Polymerase Is Essential for Hepatitis C Virus RNA Replication , 2004, Journal of Virology.

[79]  S. Nishikawa,et al.  In vitro selection of RNA aptamers against the HCV NS3 helicase domain. , 2004, Oligonucleotides.

[80]  K. Kyono,et al.  Expression and purification of a hepatitis C virus NS3/4A complex, and characterization of its helicase activity with the Scintillation Proximity Assay system. , 2004, Journal of biochemistry.

[81]  E. De Clercq,et al.  Antivirals and antiviral strategies. , 2004, Nature reviews. Microbiology.

[82]  X. Forns,et al.  Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. , 2004, Gastroenterology.

[83]  R. Garry,et al.  Inhibition of hepatitis C virus nonstructural protein, helicase activity, and viral replication by a recombinant human antibody clone. , 2004, The American journal of pathology.

[84]  S. Behrens,et al.  Synthesis and Evaluation of ATP-Binding Site Directed Potential Inhibitors of Nucleoside Triphosphatases/ Helicases and Polymerases of Hepatitis C and other Selected Flaviviridae Viruses , 2004, Antiviral chemistry & chemotherapy.

[85]  C. Cameron,et al.  Multiple Full-length NS3 Molecules Are Required for Optimal Unwinding of Oligonucleotide DNA in Vitro* , 2005, Journal of Biological Chemistry.

[86]  N. Cammack,et al.  Inhibition of native hepatitis C virus replicase by nucleotide and non-nucleoside inhibitors. , 2005, Virology.

[87]  A. Salonen,et al.  Viral RNA Replication in Association with Cellular Membranes , 2005, Current topics in microbiology and immunology.