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Chapter 12 : Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus

Authors: Dale L. Barnard1, Yohichi Kumaki2
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Affiliations: 1: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, Utah State University, Logan, UT 84322-5600; 2: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, Utah State University, Logan, UT 84322-5600
Content Type: Monograph
Publication Year: 2009

Category: Viruses and Viral Pathogenesis; Clinical Microbiology

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Abstract:

Severe acute respiratory syndrome (SARS) is the first new infectious disease of this century, caused by a novel human coronavirus (SARS-CoV), and the disease is associated with severe pulmonary pathological features leading to high mortality. This chapter talks about different kinds of inhibitors such as small-molecule inhibitors, peptide, and papain-like proteinase inhibitors. SARS-CoV is a positive-sense single-stranded (ss) RNA virus. The 30-kb genome is predicted to encode at least 10 open reading frames (ORF), some of which encode proteins involved in virus entry into cells. Receptor-virus interaction can be inhibited using two approaches. First, develop inhibitors that block the cellular receptor with which the virus attachment protein interacts. Second, block the domain in the virus attachment protein that binds to the cellular receptor. Researchers have determined the crystal structures of human coronavirus 3CL and suggested that the rhinovirus 3CL inhibitor AG7088 could serve as a starting point for an anti-SARS drug based on the theoretical homology model of SARS-CoV 3CL. Researchers have showed that the RNAi targeting of the coronavirus RdRp using synthesized short hairpin expression plasmids significantly reduced the expression of target protein in 293 cells and HeLa cells and blocked plaque formation of SARS-CoV in Vero E6 cells. Development of inhibitors of the innate immune response might also be worthwhile, with the caveat that humans, like animals, are reservoirs of mixed infections, latent, chronic, and acute, and that down-regulating an immune response to ameliorate a SARS infection may exacerbate a coexisting infection from another infectious agent.

Citation: Barnard D, Kumaki Y. 2009. Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus, p 209-222. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch12
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Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus
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Citation: Barnard D, Kumaki Y. 2009. Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus, p 209-222. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch12
/content/10.1128/9781555815493.ch12.ch12fig01
Figure 1.
Spike protein of SARS-CoV and gp41 of HIV-1 are illustrated in parallel. When they contact each other, CP-1 and NP-1 of S protein of SARS-CoV and corresponding HIV-1 protein DP-107 and DP-178 form coil structures. After the process, the conformational changes of S1 or gp41 occur and induce fusion between infected and uninfected cells.
10.1128/9781555815493/f0212-01_thmb.gif
10.1128/9781555815493/f0212-01.gif
Image of Figure 1.
Figure 1.

Spike protein of SARS-CoV and gp41 of HIV-1 are illustrated in parallel. When they contact each other, CP-1 and NP-1 of S protein of SARS-CoV and corresponding HIV-1 protein DP-107 and DP-178 form coil structures. After the process, the conformational changes of S1 or gp41 occur and induce fusion between infected and uninfected cells.

Citation: Barnard D, Kumaki Y. 2009. Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus, p 209-222. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch12
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References

/content/book/10.1128/9781555815493.ch12
1. Ahlquist, P. 2002. RNA-dependent RNA polymerases, viruses, and RNA silencing. Science 296: 1270– 1273.
2. Akerstrom, S.,, A. Mirazimi, and, Y. J. Tan. 2007. Inhibition of SARS-CoV replication cycle by small interference RNAs silencing specific SARS proteins, 7a/7b, 3a/3b and S. Antivir. Res. 73: 219– 227.
3. Anand, K.,, J. Ziebuhr,, P. Wadhwani,, J. R. Mesters, and, R. Hilgenfeld. 2003. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300: 1763– 1767.
4. Barnard, D. L.,, C. W. Day,, K. Bailey,, M. Heiner,, R. Montgomery,, L. Lauridsen,, P. K. Chan, and, R. W. Sidwell. 2006. Evaluation of immunomodulators, interferons and known in vitro SARS-CoV inhibitors for inhibition of SARS-CoV replication in BALB/c mice. Antivir. Chem. Chemother. 17: 275– 284.
5. Barnard, D. L.,, C. W. Day,, K. Bailey,, M. Heiner,, R. Montgomery,, L. Lauridsen,, S. Winslow,, J. Hoopes,, J. K. Li,, J. Lee,, D. A. Carson,, H. B. Cottam, and, R. W. Sidwell. 2006. Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin. Antivir. Res. 71: 53– 63.
6. Barnard, D. L.,, V. D. Hubbard,, J. Burton,, D. F. Smee,, J. D. Morrey,, M. J. Otto, and, R. W. Sidwell. 2004. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) by calpain inhibitors and beta-D-N4-hydroxycytidine. Antivir. Chem. Chemother. 15: 15– 22.
7. Barretto, N.,, D. Jukneliene,, K. Ratia,, Z. Chen,, A. D. Mesecar, and, S. C. Baker. 2006. Deubiquitinating activity of the SARSCoV papain-like protease. Adv. Exp. Med. Biol. 581: 37– 41.
8. Bartlam, M.,, Y. Xu, and, Z. Rao. 2007. Structural proteomics of the SARS coronavirus: a model response to emerging infectious diseases. J. Struct. Funct. Genomics 8: 85– 97.
9. Bartlam, M.,, H. Yang, and, Z. Rao. 2005. Structural insights into SARS coronavirus proteins. Curr. Opin. Struct. Biol. 15: 664– 672.
10. Bhardwaj, K.,, L. Guarino, and, C. C. Kao. 2004. The severe acute respiratory syndrome coronavirus Nsp15 protein is an endoribonuclease that prefers manganese as a cofactor. J. Virol. 78: 12218– 12224.
11. Bhardwaj, K.,, J. Sun,, A. Holzenburg,, L. A. Guarino, and, C. C. Kao. 2006. RNA recognition and cleavage by the SARS coronavirus endoribonuclease. J. Mol. Biol. 361: 243– 256.
12. Booth, C. M.,, L. M. Matukas,, G. A. Tomlinson,, A. R. Rachlis,, D. B. Rose,, H. A. Dwosh,, S. L. Walmsley,, T. Mazzulli,, M. Avendano,, P. Derkach,, I. E. Ephtimios,, I. Kitai,, B. D. Mederski,, S. B. Shadowitz,, W. L. Gold,, L. A. Hawryluck,, E. Rea,, J. S. Chenkin,, D. W. Cescon,, S. M. Poutanen, and, A. S. Detsky. 2003. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 289: 2801– 2809.
13. Bosch, B. J.,, B. E. Martina,, R. Van Der Zee,, J. Lepault,, B. J. Haijema,, C. Versluis,, A. J. Heck,, R. De Groot,, A. D. Osterhaus, and, P. J. Rottier. 2004. Severe acute respiratory syndrome corona-virus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides. Proc. Natl. Acad. Sci. USA 101: 8455– 8460.
14. Bosch, B. J.,, R. van der Zee,, C. A. de Haan, and, P. J. Rottier. 2003. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J. Virol. 77: 8801– 8811.
15. Chan, C. M.,, C. W. Ma,, W. Y. Chan, and, H. Y. Chan. 2007. The SARS-coronavirus membrane protein induces apoptosis through modulating the Akt survival pathway. Arch. Biochem. Biophys. 459: 197– 207.
16. Chan, J. W.,, C. K. Ng,, Y. H. Chan,, T. Y. Mok,, S. Lee,, S. Y. Chu,, W. L. Law,, M. P. Lee, and, P. C. Li. 2003. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). Thorax 58: 686– 689.
17. Chen, C. Y.,, C. K. Chang,, Y. W. Chang,, S. C. Sue,, H. I. Bai,, L. Riang,, C. D. Hsiao, and, T. H. Huang. 2007. Structure of the SARS coronavirus nucleocapsid protein RNA-binding dimerization domain suggests a mechanism for helical packaging of viral RNA. J. Mol. Biol. 368: 1075– 1086.
18. Chen, F.,, K. H. Chan,, Y. Jiang,, R. Y. Kao,, H. T. Lu,, K. W. Fan,, V. C. Cheng,, W. H. Tsui,, I. F. Hung,, T. S. Lee,, Y. Guan,, J. S. Peiris, and, K. Y. Yuen. 2004. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J. Clin. Virol. 31: 69– 75.
19. Chen, P.,, M. Jiang,, T. Hu,, Q. Liu,, X. S. Chen, and, D. Guo. 2007. Biochemical characterization of exoribonuclease encoded by SARS coronavirus. J. Biochem. Mol. Biol. 40: 649– 655.
20. Chen, S.,, H. Luo,, L. Chen,, J. Chen,, J. Shen,, W. Zhu,, K. Chen,, X. Shen, and, H. Jiang. 2006. An overall picture of SARS coronavirus (SARS-CoV) genome-encoded major proteins: structures, functions and drug development. Curr. Pharm. Des. 12: 4539– 4553.
21. Chen, Z.,, L. Zhang,, C. Qin,, L. Ba,, C. E. Yi,, F. Zhang,, Q. Wei,, T. He,, W. Yu,, J. Yu,, H. Gao,, X. Tu,, A. Gettie,, M. Farzan,, K. Y. Yuen, and, D. D. Ho. 2005. Recombinant modified vaccinia virus Ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region. J. Virol. 79: 2678– 2688.
22. Chinese SARS Molecular Epidemiology Consortium. 2004. Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China. Science 303: 1666– 1669.
23. Chou, K. C.,, D. Q. Wei, and, W. Z. Zhong. 2003. Binding mechanism of coronavirus main proteinase with ligands and its implication to drug design against SARS. Biochem. Biophys. Res. Commun. 308: 148– 151.
24. Cinatl, J.,, B. Morgenstern,, G. Bauer,, P. Chandra,, H. Rabenau, and, H. W. Doerr. 2003. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 361: 2045– 2046.
25. Cinatl, J.,, B. Morgenstern,, G. Bauer,, P. Chandra,, H. Rabenau, and, H. W. Doerr. 2003. Treatment of SARS with human interferons. Lancet 362: 293– 294.
26. Connor, R. F., and, R. L. Roper. 2007. Unique SARS-CoV protein nsp1: bioinformatics, biochemistry and potential effects on virulence. Trends Microbiol. 15: 51– 53.
27. De Clercq, E. 2006. Potential antivirals and antiviral strategies against SARS coronavirus infections. Expert Rev. Anti. Infect. Ther. 4: 291– 302.
28. Deng, Y.,, J. Liu,, Q. Zheng,, W. Yong, and, M. Lu. 2006. Structures and polymorphic interactions of two heptad-repeat regions of the SARS virus S2 protein. Structure 14: 889– 899.
29. Domingo, E. 1998. Quasispecies and the implications for virus persistence and escape. Clin. Diagn. Virol. 10: 97– 101.
30. Du, Q.,, S. Wang,, D. Wei,, S. Sirois, and, K. C. Chou. 2005. Molecular modeling and chemical modification for finding peptide inhibitor against severe acute respiratory syndrome coronavirus main proteinase. Anal. Biochem. 337: 262– 270.
31. Du, Q. S.,, H. Sun, and, K. C. Chou. 2007. Inhibitor design for SARS coronavirus main protease based on “distorted key theory.” Med. Chem. 3: 1– 6.
32. Du, Q. S.,, S. Q. Wang,, Y. Zhu,, D. Q. Wei,, H. Guo,, S. Sirois, and, K. C. Chou. 2004. Polyprotein cleavage mechanism of SARS CoV Mpro and chemical modification of the octapeptide. Peptides 25: 1857– 1864.
33. Elbashir, S. M.,, J. Harborth,, W. Lendeckel,, A. Yalcin,, K. Weber, and, T. Tuschl. 2001. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411: 494– 498.
34. Fan, K.,, P. Wei,, Q. Feng,, S. Chen,, C. Huang,, L. Ma,, B. Lai,, J. Pei,, Y. Liu,, J. Chen, and, L. Lai. 2004. Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome corona-virus 3C-like proteinase. J. Biol. Chem. 279: 1637– 1642.
35. Fan, Z.,, K. Peng,, X. Tan,, B. Yin,, X. Dong,, F. Qiu,, Y. Shen,, H. Wang,, J. Yuan,, B. Qiang, and, X. Peng. 2005. Molecular cloning, expression, and purification of SARS-CoV nsp13. Protein Expr. Purif. 41: 235– 240.
36. Fang, X.,, J. Gao,, H. Zheng,, B. Li,, L. Kong,, Y. Zhang,, W. Wang,, Y. Zeng, and, L. Ye. 2007. The membrane protein of SARS-CoV suppresses NF-kappaB activation. J. Med. Virol. 79: 1431– 1439.
37. Fire, A.,, S. Xu,, M. K. Montgomery,, S. A. Kostas,, S. E. Driver, and, C. C. Mello. 1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391: 806– 811.
38. Gan, Y. R.,, H. Huang,, Y. D. Huang,, C. M. Rao,, Y. Zhao,, J. S. Liu,, L. Wu, and, D. Q. Wei. 2006. Synthesis and activity of an octapep-tide inhibitor designed for SARS coronavirus main proteinase. Peptides 27: 622– 625.
39. Gao, F.,, H. Y. Ou,, L. L. Chen,, W. X. Zheng, and, C. T. Zhang. 2003. Prediction of proteinase cleavage sites in polyproteins of coronaviruses and its applications in analyzing SARS-CoV genomes. FEBS Lett. 553: 451– 456.
40. Gibson, I. 1994. Antisense DNA and RNA strategies: new approaches to therapy. J. R. Coll. Physicians Lond. 28: 507– 511.
41. Ginalski, K.,, A. Godzik, and, L. Rychlewski. 2006. Novel SARS unique AdoMet-dependent methyltransferase. Cell Cycle 5: 2414– 2416.
42. Glass, W. G.,, K. Subbarao,, B. Murphy, and, P. M. Murphy. 2004. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J. Immunol. 173: 4030– 4039.
43. Graham, R. L.,, A. C. Sims,, R. S. Baric, and, M. R. Denison. 2006. The nsp2 proteins of mouse hepatitis virus and SARS corona-virus are dispensable for viral replication. Adv. Exp. Med. Biol. 581: 67– 72.
44. Graziano, V.,, W. J. McGrath,, A. M. DeGruccio,, J. J. Dunn, and, W. F. Mangel. 2006. Enzymatic activity of the SARS coronavirus main proteinase dimer. FEBS Lett. 580: 2577– 2583.
45. Groneberg, D. A.,, A. Fischer,, K. F. Chung, and, H. Daniel. 2004. Molecular mechanisms of pulmonary peptidomimetic drug and peptide transport. Am. J. Respir. Cell Mol. Biol. 30: 251– 260.
46. Groneberg, D. A.,, C. Witt,, U. Wagner,, K. F. Chung, and, A. Fischer. 2003. Fundamentals of pulmonary drug delivery. Respir. Med. 97: 382– 387.
47. Guan, Y.,, B. J. Zheng,, Y. Q. He,, X. L. Liu,, Z. X. Zhuang,, C. L. Cheung,, S. W. Luo,, P. H. Li,, L. J. Zhang,, Y. J. Guan,, K. M. Butt,, K. L. Wong,, K. W. Chan,, W. Lim,, K. F. Shortridge,, K. Y. Yuen,, J. S. Peiris, and, L. L. Poon. 2003. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 302: 276– 278.
48. Han, D. P.,, A. Penn-Nicholson, and, M. W. Cho. 2006. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology 350: 15– 25.
49. Han, Y. S.,, G. G. Chang,, C. G. Juo,, H. J. Lee,, S. H. Yeh,, J. T. Hsu, and, X. Chen. 2005. Papain-like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition. Biochemistry 44: 10349– 10359.
50. He, R.,, A. Adonov,, M. Traykova-Adonova,, J. Cao,, T. Cutts,, E. Grudesky,, Y. Deschambaul,, J. Berry,, M. Drebot, and, X. Li. 2004. Potent and selective inhibition of SARS coronavirus replication by aurintricarboxylic acid. Biochem. Biophys. Res. Commun. 320: 1199– 1203.
51. Ho, T. Y.,, S. L. Wu,, J. C. Chen,, Y. C. Wei,, S. E. Cheng,, Y. H. Chang,, H. J. Liu, and, C. Y. Hsiang. 2006. Design and biological activities of novel inhibitory peptides for SARS-CoV spike protein and angiotensin-converting enzyme 2 interaction. Antivir. Res. 69: 70– 76.
52. Hofmann, H.,, M. Geier,, A. Marzi,, M. Krumbiegel,, M. Peipp,, G. H. Fey,, T. Gramberg, and, S. Pohlmann. 2004. Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor. Biochem. Biophys. Res. Commun. 319: 1216– 1221.
53. Hofmann, H.,, K. Hattermann,, A. Marzi,, T. Gramberg,, M. Geier,, M. Krumbiegel,, S. Kuate,, K. Uberla,, M. Niedrig, and, S. Pohl-mann. 2004. S protein of severe acute respiratory syndrome-associated coronavirus mediates entry into hepatoma cell lines and is targeted by neutralizing antibodies in infected patients. J. Virol. 78: 6134– 6142.
54. Huang, C.,, N. Ito,, C.-T. K. Tseng, and, S. Makino. 2006. Severe acute respiratory syndrome coronavirus 7a accessory protein is a viral structural protein. J. Virol. 80: 7287– 7294.
55. Huentelman, M. J.,, J. Zubcevic,, J. A. Hernandez Prada,, X. Xiao,, D. S. Dimitrov,, M. K. Raizada, and, D. A. Ostrov. 2004. Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor. Hypertension 44: 903– 906.
56. Imbert, I.,, J. C. Guillemot,, J. M. Bourhis,, C. Bussetta,, B. Coutard,, M. P. Egloff,, F. Ferron,, A. E. Gorbalenya, and, B. Canard. 2006. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 25: 4933– 4942.
57. Ivanov, K. A.,, V. Thiel,, J. C. Dobbe,, Y. van der Meer,, E. J. Snijder, and, J. Ziebuhr. 2004. Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. J. Virol. 78: 5619– 5632.
58. Jackwood, M. W. 2006. The relationship of severe acute respiratory syndrome coronavirus with avian and other coronaviruses. Avian Dis. 50: 315– 320.
59. Jamjian, M. C., and, I. R. McNicholl. 2004. Enfuvirtide: first fusion inhibitor for treatment of HIV infection. Am. J. Health Syst. Pharm. 61: 1242– 1247.
60. Jeffers, S. A.,, S. M. Tusell,, L. Gillim-Ross,, E. M. Hemmila,, J. E. Achenbach,, G. J. Babcock,, W. D. Thomas, Jr.,, L. B. Thackray,, M. D. Young,, R. J. Mason,, D. M. Ambrosino,, D. E. Wentworth,, J. C. Demartini, and, K. V. Holmes. 2004. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc. Natl. Acad. Sci. USA 101: 15748– 15753.
61. Johnson-Saliba, M., and, D. A. Jans. 2001. Gene therapy: optimising DNA delivery to the nucleus. Curr. Drug Targets 2: 371– 399.
62. Joseph, J. S.,, K. S. Saikatendu,, V. Subramanian,, B. W. Neuman,, A. Brooun,, M. Griffith,, K. Moy,, M. K. Yadav,, J. Velasquez,, M. J. Buchmeier,, R. C. Stevens, and, P. Kuhn. 2006. Crystal structure of nonstructural protein 10 from the severe acute respiratory syndrome coronavirus reveals a novel fold with two zinc-binding motifs. J. Virol. 80: 7894– 7901.
63. Kamitani, W.,, K. Narayanan,, C. Huang,, K. Lokugamage,, T. Ikegami,, N. Ito,, H. Kubo, and, S. Makino. 2006. Severe acute respiratory syndrome coronavirus Nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc. Natl. Acad. Sci. USA 103: 12885– 12890.
64. Kao, R. Y.,, W. H. Tsui,, T. S. Lee,, J. A. Tanner,, R. M. Watt,, J. D. Huang,, L. Hu,, G. Chen,, Z. Chen,, L. Zhang,, T. He,, K. H. Chan,, H. Tse,, A. P. To,, L. W. Ng,, B. C. Wong,, H. W. Tsoi,, D. Yang,, D. D. Ho, and, K. Y. Yuen. 2004. Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics. Chem. Biol. 11: 1293– 1299.
65. Keller, T. H.,, A. Pichota, and, Z. Yin. 2006. A practical view of ‘druggability’. Curr. Opin. Chem. Biol. 10: 357– 361.
66. Keng, C. T.,, A. Zhang,, S. Shen,, K. M. Lip,, B. C. Fielding,, T. H. Tan,, C. F. Chou,, C. B. Loh,, S. Wang,, J. Fu,, X. Yang,, S. G. Lim,, W. Hong, and, Y. J. Tan. 2005. Amino acids 1055 to 1192 in the S2 region of severe acute respiratory syndrome coronavirus S protein induce neutralizing antibodies: implications for the development of vaccines and antiviral agents. J. Virol. 79: 3289– 3296.
67. Kesel, A. J. 2005. Synthesis of novel test compounds for antiviral chemotherapy of severe acute respiratory syndrome (SARS). Curr. Med. Chem. 12: 2095– 2162.
68. Keyaerts, E.,, L. Vijgen,, P. Maes,, J. Neyts, and, M. Van Ranst. 2004. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem. Biophys. Res. Commun. 323: 264– 268.
69. Keyaerts, E.,, L. Vijgen, and, M. van Ranst. 2007. Current status of antiviral severe acute respiratory syndrome coronavirus research, p. 321–346. In V. Thiel (ed.), Coronaviruses: Molecular and Cellular Biology. Caister Academic Press, Norfolk, United Kingdom.
70. Kopecky-Bromberg, S. A.,, L. Martinez-Sobrido,, M. Frieman,, R. A. Baric, and, P. Palese. 2006. Coronavirus proteins open reading frame (ORF) 3b, ORF 6, and nucleocapsid function as inter-feron antagonists. J. Virol. 81: 548– 557.
71. Ksiazek, T. G.,, D. Erdman,, C. S. Goldsmith,, S. R. Zaki,, T. Peret,, S. Emery,, S. Tong,, C. Urbani,, J. A. Comer,, W. Lim,, P. E. Rollin,, S. F. Dowell,, A. E. Ling,, C. D. Humphrey,, W. J. Shieh,, J. Guarner,, C. D. Paddock,, P. Rota,, B. Fields,, J. DeRisi,, J. Y. Yang,, N. Cox,, J. M. Hughes,, J. W. LeDuc,, W. J. Bellini, and, L. J. Anderson. 2003. A novel coronavirus associated with severe acute respiratory syndrome. N. Engl. J. Med. 348: 1953– 1966.
72. Kumar, P.,, V. Gunalan,, B. Liu,, V. T. Chow,, J. Druce,, C. Birch,, M. Catton,, B. C. Fielding,, Y. J. Tan, and, S. K. Lal. 2007. The nonstructural protein 8 (Nsp8) of the SARS coronavirus interacts with its ORF6 accessory protein. Virology 366: 293– 303.
73. Lai, C. C.,, M. J. Jou,, S. Y. Huang,, S. W. Li,, L. Wan,, F. J. Tsai, and, C. W. Lin. 2007. Proteomic analysis of up-regulated proteins in human promonocyte cells expressing severe acute respiratory syndrome coronavirus 3C-like protease. Proteomics 7: 1446– 1460.
74. Li, B. J.,, Q. Tang,, D. Cheng,, C. Qin,, F. Y. Xie,, Q. Wei,, J. Xu,, Y. Liu,, B. J. Zheng,, M. C. Woodle,, N. Zhong, and, P. Y. Lu. 2005. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat. Med. 11: 944– 951.
75. Li, F.,, M. Berardi,, W. Li,, M. Farzan,, P. R. Dormitzer, and, S. C. Harrison. 2006. Conformational states of the severe acute respiratory syndrome coronavirus spike protein ectodomain. J. Virol. 80: 6794– 6800.
76. Li, Q.,, L. Wang,, C. Dong,, Y. Che,, L. Jiang,, L. Liu,, H. Zhao,, Y. Liao,, Y. Sheng,, S. Dong, and, S. Ma. 2005. The interaction of the SARS coronavirus non-structural protein 10 with the cellular oxido-reductase system causes an extensive cytopathic effect. J. Clin. Virol. 34: 133– 139.
77. Li, T.,, Y. Zhang,, L. Fu,, C. Yu,, X. Li,, Y. Li,, X. Zhang,, Z. Rong,, Y. Wang,, H. Ning,, R. Liang,, W. Chen,, L. A. Babiuk, and, Z. Chang. 2005. siRNA targeting the leader sequence of SARS-CoV inhibits virus replication. Gene Ther. 12: 751– 761.
78. Li, W.,, M. J. Moore,, N. Vasilieva,, J. Sui,, S. K. Wong,, M. A. Berne,, M. Somasundaran,, J. L. Sullivan,, K. Luzuriaga,, T. C. Greenough,, H. Choe, and, M. Farzan. 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426: 450– 454.
79. Liang, P. H. 2006. Characterization and inhibition of SARS-coronavirus main protease. Curr. Top. Med. Chem. 6: 361– 376.
80. Lindner, H. A.,, V. Lytvyn,, H. Qi,, P. Lachance,, E. Ziomek, and, R. Menard. 2007. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch. Biochem. Biophys. 466: 8– 14.
81. Liu, S.,, G. Xiao,, Y. Chen,, Y. He,, J. Niu,, C. R. Escalante,, H. Xiong,, J. Farmar,, A. K. Debnath,, P. Tien, and, S. Jiang. 2004. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet 363: 938– 947.
82. Lu, A.,, H. Zhang,, X. Zhang,, H. Wang,, Q. Hu,, L. Shen,, B. S. Schaffhausen,, W. Hou, and, L. Li. 2004. Attenuation of SARS coronavirus by a short hairpin RNA expression plasmid targeting RNA-dependent RNA polymerase. Virology 324: 84– 89.
83. Lu, W.,, B. J. Zheng,, K. Xu,, W. Schwarz,, L. Du,, C. K. Wong,, J. Chen,, S. Duan,, V. Deubel, and, B. Sun. 2006. Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proc. Natl. Acad. Sci. USA 103: 12540– 12545.
84. Marra, M. A.,, S. J. Jones,, C. R. Astell,, R. A. Holt,, A. Brooks-Wilson,, Y. S. Butterfield,, J. Khattra,, J. K. Asano,, S. A. Barber,, S. Y. Chan,, A. Cloutier,, S. M. Coughlin,, D. Freeman,, N. Girn,, O. L. Griffith,, S. R. Leach,, M. Mayo,, H. McDonald,, S. B. Montgomery,, P. K. Pandoh,, A. S. Petrescu,, A. G. Robertson,, J. E. Schein,, A. Siddiqui,, D. E. Smailus,, J. M. Stott,, G. S. Yang,, F. Plummer,, A. Andonov,, H. Artsob,, N. Bastien,, K. Bernard,, T. F. Booth,, D. Bowness,, M. Czub,, M. Drebot,, L. Fernando,, R. Flick,, M. Gar-butt,, M. Gray,, A. Grolla,, S. Jones,, H. Feldmann,, A. Meyers,, A. Kabani,, Y. Li,, S. Normand,, U. Stroher,, G. A. Tipples,, S. Tyler,, R. Vogrig,, D. Ward,, B. Watson,, R. C. Brunham,, M. Krajden,, M. Petric,, D. M. Skowronski,, C. Upton, and, R. L. Roper. 2003. The genome sequence of the SARS-associated coronavirus. Science 300: 1399– 1404.
85. Meier, C.,, A. R. Aricescu,, R. Assenberg,, R. T. Aplin,, R. J. Gilbert,, J. M. Grimes, and, D. I. Stuart. 2006. The crystal structure of ORF-9b, a lipid binding protein from the SARS coronavirus. Structure 14: 1157– 1165.
86. Minskaia, E.,, T. Hertzig,, A. E. Gorbalenya,, V. Campanacci,, C. Cambillau,, B. Canard, and, J. Ziebuhr. 2006. Discovery of an RNA virus 3’l5’ exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc. Natl. Acad. Sci. USA 103: 5108– 5113.
87. Moore, M. J.,, T. Dorfman,, W. Li,, S. K. Wong,, Y. Li,, J. H. Kuhn,, J. Coderre,, N. Vasilieva,, Z. Han,, T. C. Greenough,, M. Farzan, and, H. Choe. 2004. Retroviruses pseudotyped with the severe acute respiratory syndrome coronavirus spike protein efficiently infect cells expressing angiotensin-converting enzyme 2. J. Virol. 78: 10628– 10635.
88. Morgenstern, B.,, M. Michaelis,, P. C. Baer,, H. W. Doerr, and, J. Cinatl, Jr. 2005. Ribavirin and interferon-beta synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. Biochem. Biophys. Res. Commun. 326: 905– 908.
89. Netland, J.,, D. Ferraro,, L. Pewe,, H. Olivares,, T. Gallagher, and, S. Perlman. 2007. Enhancement of murine coronavirus replication by SARS-CoV protein 6 requires the N-terminal hydrophobic region but not C-terminal sorting motifs. J. Virol. 81: 11520– 11525.
90. Neuman, B. W.,, D. A. Stein,, A. D. Kroeker,, H. M. Moulton,, R. K. Bestwick,, P. L. Iversen, and, M. J. Buchmeier. 2006. Inhibition and escape of SARS-CoV treated with antisense morpholino oligomers. Adv. Exp. Med. Biol. 581: 567– 571.
91. Ni, B.,, X. Shi,, Y. Li,, W. Gao,, X. Wang, and, Y. Wu. 2005. Inhibition of replication and infection of severe acute respiratory syndrome-associated coronavirus with plasmid-mediated interference RNA. Antivir. Ther. 10: 527– 533.
92. Ni, L.,, J. Zhu,, J. Zhang,, M. Yan,, G. F. Gao, and, P. Tien. 2005. Design of recombinant protein-based SARS-CoV entry inhibitors targeting the heptad-repeat regions of the spike protein S2 domain. Biochem. Biophys. Res. Commun. 330: 39– 45.
93. Oostra, M.,, C. A. M. de Haan, and, P. J. M. Rottier. 2007. The 29-nucleotide deletion present in human but not in animal SARS coronaviruses disrupts the functional expression of open reading frame 8. J. Virol. 81: 13876– 13888.
94. Oostra, M.,, E. G. te Lintelo,, M. Deijs,, M. H. Verheije,, P. J. M. Rottier, and, C. A. M. de Haan. 2007. Localization and membrane topology of the coronavirus nonstructural protein 4: involvement of the early secretory pathway in replication. J. Virol. 81: 12323– 12336.
95. Pang, R. T. K.,, T. C. W. Poon,, K. C. A. Chan,, N. L. S. Lee,, R. W. K. Chiu,, Y.-K. Tong,, R. M. Y. Wong,, S. S. C. Chim,, S. M. Ngai,, J. J. Y. Sung, and, Y. M. D. Lo. 2006. Serum proteomic fingerprints of adult patients with severe acute respiratory syndrome. Clin. Chem. 52: 421– 429.
96. Peiris, J. S.,, S. T. Lai,, L. L. Poon,, Y. Guan,, L. Y. Yam,, W. Lim,, J. Nicholls,, W. K. Yee,, W. W. Yan,, M. T. Cheung,, V. C. Cheng,, K. H. Chan,, D. N. Tsang,, R. W. Yung,, T. K. Ng, and, K. Y. Yuen. 2003. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361: 1319– 1325.
97. Prentice, E.,, J. McAuliffe,, X. Lu,, K. Subbarao, and, M. R. Denison. 2004. Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins. J. Virol. 78: 9977– 9986.
98. Qin, Z. L.,, P. Zhao,, M. M. Cao, and, Z. T. Qi. 2007. siRNAs targeting terminal sequences of the SARS-associated coronavirus membrane gene inhibit M protein expression through degradation of M mRNA. J. Virol. Methods 145: 146– 154.
99. Qin, Z. L.,, P. Zhao,, X. L. Zhang,, J. G. Yu,, M. M. Cao,, L. J. Zhao,, J. Luan, and, Z. T. Qi. 2004. Silencing of SARS-CoV spike gene by small interfering RNA in HEK 293T cells. Biochem. Biophys. Res. Commun. 324: 1186– 1193.
100. Roberts, A.,, D. Deming,, C. D. Paddock,, A. Cheng,, B. Yount,, L. Vogel,, B. D. Herman,, T. Sheahan,, M. Heise,, G. L. Genrich,, S. R. Zaki,, R. Baric, and, K. Subbarao. 2007. A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog. 3: e5.
101. Rota, P. A.,, M. S. Oberste,, S. S. Monroe,, W. A. Nix,, R. Campagnoli,, J. P. Icenogle,, S. Penaranda,, B. Bankamp,, K. Maher,, M. H. Chen,, S. Tong,, A. Tamin,, L. Lowe,, M. Frace,, J. L. DeRisi,, Q. Chen,, D. Wang,, D. D. Erdman,, T. C. Peret,, C. Burns,, T. G. Ksiazek,, P. E. Rollin,, A. Sanchez,, S. Liffick,, B. Holloway,, J. Limor,, K. McCaustland,, M. Olsen-Rasmussen,, R. Fouchier,, S. Gunther,, A. D. Osterhaus,, C. Drosten,, M. A. Pallansch,, L. J. Anderson, and, W. J. Bellini. 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300: 1394– 1399.
102. Saijo, M.,, S. Morikawa,, S. Fukushi,, T. Mizutani,, H. Hasegawa,, N. Nagata,, N. Iwata, and, I. Kurane. 2005. Inhibitory effect of mizoribine and ribavirin on the replication of severe acute respiratory syndrome (SARS)-associated coronavirus. Antivir. Res. 66: 159– 163.
103. Saikatendu, K. S.,, J. S. Joseph,, V. Subramanian,, T. Clayton,, M. Griffith,, K. Moy,, J. Velasquez,, B. W. Neuman,, M. J. Buch-meier,, R. C. Stevens, and, P. Kuhn. 2005. Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1’-phosphate dephosphorylation by a conserved domain of nsP3. Structure 13: 1665– 1675.
104. Saikatendu, K. S.,, J. S. Joseph,, V. Subramanian,, B. W. Neuman,, M. J. Buchmeier,, R. C. Stevens, and, P. Kuhn. 2007. Ribonucleocapsid formation of severe acute respiratory syndrome coronavirus through molecular action of the N-terminal domain of N protein. J. Virol. 81: 3913– 3921.
105. Satija, N., and, S. K. Lal. 2007. The molecular biology of SARS coronavirus. Ann. N. Y. Acad. Sci. 1102: 26– 38.
106. Savarino, A.,, J. R. Boelaert,, A. Cassone,, G. Majori, and, R. Cauda. 2003. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect. Dis. 3: 722– 727.
107. Schaecher, S. R.,, J. M. Mackenzie, and, A. Pekosz. 2007. The ORF7b protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is expressed in virus-infected cells and incorporated into SARS-CoV particles. J. Virol. 81: 718– 731.
108. Shen, S.,, P. S. Lin,, Y. C. Chao,, A. Zhang,, X. Yang,, S. G. Lim,, W. Hong, and, Y. J. Tan. 2005. The severe acute respiratory syndrome coronavirus 3a is a novel structural protein. Biochem. Biophys. Res. Commun. 330: 286– 292.
109. Shi, Y.,, H. Luo,, J. Jia,, J. Xiong,, D. Yang,, B. Huang, and, Y. Jin. 2005. Antisense downregulation of SARS-CoV gene expression in Vero E6 cells. J. Gene Med. 7: 97– 107.
110. Shi, Y.,, D. H. Yang,, J. Xiong,, J. Jia,, B. Huang, and, Y. X. Jin. 2005. Inhibition of genes expression of SARS coronavirus by synthetic small interfering RNAs. Cell Res. 15: 193– 200.
111. Simmons, G.,, D. N. Gosalia,, A. J. Rennekamp,, J. D. Reeves,, S. L. Diamond, and, P. Bates. 2005. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc. Natl. Acad. Sci. USA 102: 11876– 11881.
112. Simmons, G.,, J. D. Reeves,, A. J. Rennekamp,, S. M. Amberg,, A. J. Piefer, and, P. Bates. 2004. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc. Natl. Acad. Sci. USA 101: 4240– 4245.
113. Snijder, E. J.,, P. J. Bredenbeek,, J. C. Dobbe,, V. Thiel,, J. Ziebuhr,, L. L. Poon,, Y. Guan,, M. Rozanov,, W. J. Spaan, and, A. E. Gorbalenya. 2003. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J. Mol. Biol. 331: 991– 1004.
114. So, L. K.,, A. C. Lau,, L. Y. Yam,, T. M. Cheung,, E. Poon,, R. W. Yung, and, K. Y. Yuen. 2003. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet 361: 1615– 1617.
115. Subbarao, K., and, A. Roberts. 2006. Is there an ideal animal model for SARS? Trends Microbiol. 14: 299– 303.
116. Sui, J.,, W. Li,, A. Murakami,, A. Tamin,, L. J. Matthews,, S. K. Wong,, M. J. Moore,, A. S. Tallarico,, M. Olurinde,, H. Choe,, L. J. Anderson,, W. J. Bellini,, M. Farzan, and, W. A. Marasco. 2004. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc. Natl. Acad. Sci. USA 101: 2536– 2541.
117. Tangudu, C.,, H. Olivares,, J. Netland,, S. Perlman, and, T. Gallagher. 2006. Severe acute respiratory syndrome coronavirus protein 6 accelerates murine coronavirus infections. J. Virol. 81: 1220– 1229.
118. Tanner, J. A.,, R. M. Watt,, Y. B. Chai,, L. Y. Lu,, M. C. Lin,, J. S. Peiris,, L. L. Poon,, H. F. Kung, and, J. D. Huang. 2003. The severe acute respiratory syndrome (SARS) coronavirus NTPase/ helicase belongs to a distinct class of 5’ to 3’ viral helicases. J. Biol. Chem. 278: 39578– 39582.
119. Tanner, J. A.,, B. J. Zheng,, J. Zhou,, R. M. Watt,, J. Q. Jiang,, K. L. Wong,, Y. P. Lin,, L. Y. Lu,, M. L. He,, H. F. Kung,, A. J. Kesel, and, J. D. Huang. 2005. The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus. Chem. Biol. 12: 303– 311.
120. Towler, P.,, B. Staker,, S. G. Prasad,, S. Menon,, J. Tang,, T. Parsons,, D. Ryan,, M. Fisher,, D. Williams,, N. A. Dales,, M. A. Patane, and, M. W. Pantoliano. 2004. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J. Biol. Chem. 279: 17996– 18007.
121. Tsang, K., and, W. H. Seto. 2004. Severe acute respiratory syndrome: scientific and anecdotal evidence for drug treatment. Curr. Opin. Investig. Drugs 5: 179– 185.
122. Vincent, M.,, E. Bergeron,, S. Benjannet,, B. Erickson,, P. Rollin,, T. Ksiazek,, N. Seidah, and, S. Nichol. 2005. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol. J. 2: 69.
123. von Brunn, A. 2007. Analysis of intraviral protein-protein interactions of the SARS coronavirus ORFeome. PLoS ONE 2: e459.
124. Wang, L. F., and, B. T. Eaton. 2007. Bats, civets and the emergence of SARS. Curr. Top. Microbiol. Immunol. 315: 325– 344.
125. Wang, S. Q.,, Q. S. Du,, K. Zhao,, A. X. Li,, D. Q. Wei, and, K. C. Chou. 2007. Virtual screening for finding natural inhibitor against cathepsin-L for SARS therapy. Amino Acids 33: 129– 135.
126. Wang, Z.,, L. Ren,, X. Zhao,, T. Hung,, A. Meng,, J. Wang, and, Y. G. Chen. 2004. Inhibition of severe acute respiratory syndrome virus replication by small interfering RNAs in mammalian cells. J. Virol. 78: 7523– 7527.
127. Wathelet, M. G.,, M. Orr,, M. B. Frieman, and, R. S. Baric. 2007. Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J. Virol. 81: 11620– 11633.
128. Waye, M. M.,, P. W. Law,, C. H. Wong,, T. C Au,, C. P. Chuck,, S. K. Kong,, P. S Chan,, K. F. To,, A. I. Lo,, J. W Chan,, Y. K. Suen,, H. Y. Chan,, K. P. Fung,, J. Y Sung,, Y. M. Lo, and, S. W. Tsui. 2005. The 3a protein of SARS-coronavirus induces apoptosis in Vero E6 cells. Conf. Proc. IEEE Eng. Med. Biol. Soc. 7: 7482– 7485.
129. Wei, P.,, K. Fan,, H. Chen,, L. Ma,, C. Huang,, L. Tan,, D. Xi,, C. Li,, Y. Liu,, A. Cao, and, L. Lai. 2006. The N-terminal octapeptide acts as a dimerization inhibitor of SARS coronavirus 3C-like proteinase. Biochem. Biophys. Res. Commun. 339: 865– 872.
130. Wong, S. K.,, W. Li,, M. J. Moore,, H. Choe, and, M. Farzan. 2004. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J. Biol. Chem. 279: 3197– 3201.
131. Wu, C. J.,, H. W. Huang,, C. Y. Liu,, C. F. Hong, and, Y. L. Chan. 2005. Inhibition of SARS-CoV replication by siRNA. Antivir. Res. 65: 45– 48.
132. Wu, C. Y.,, J. T. Jan,, S. H. Ma,, C. J. Kuo,, H. F. Juan,, Y. S. Cheng,, H. H. Hsu,, H. C. Huang,, D. Wu,, A. Brik,, F. S. Liang,, R. S. Liu,, J. M. Fang,, S. T. Chen,, P. H. Liang, and, C. H. Wong. 2004. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc. Natl. Acad. Sci. USA 101: 10012– 10017.
133. Wu, X. D.,, B. Shang,, R. F. Yang,, H. Yu,, Z. H. Ma,, X. Shen,, Y. Y. Ji,, Y. Lin,, Y. D. Wu,, G. M. Lin,, L. Tian,, X. Q. Gan,, S. Yang,, W. H. Jiang,, E. H. Dai,, X. Y. Wang,, H. L. Jiang,, Y. H. Xie,, X. L. Zhu,, G. Pei,, L. Li,, J. R. Wu, and, B. Sun. 2004. The spike protein of severe acute respiratory syndrome (SARS) is cleaved in virus infected Vero-E6 cells. Cell Res. 14: 400– 406.
134. Xi, X. G. 2007. Helicases as antiviral and anticancer drug targets. Curr. Med. Chem. 14: 883– 915.
135. Yan, L.,, M. Velikanov,, P. Flook,, W. Zheng,, S. Szalma, and, S. Kahn. 2003. Assessment of putative protein targets derived from the SARS genome. FEBS Lett. 554: 257– 263.
136. Yang, H.,, M. Bartlam, and, Z. Rao. 2006. Drug design targeting the main protease, the Achilles’ heel of coronaviruses. Curr. Pharm. Des. 12: 4573– 4590.
137. Yang, H.,, M. Yang,, Y. Ding,, Y. Liu,, Z. Lou,, Z. Zhou,, L. Sun,, L. Mo,, S. Ye,, H. Pang,, G. F. Gao,, K. Anand,, M. Bartlam,, R. Hilgenfeld, and, Z. Rao. 2003. The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc. Natl. Acad. Sci. USA 100: 13190– 13195.
138. Yeung, K.-S., and, N. A. Meanwell. 2007. Recent developments in the virology and antiviral research of severe acute respiratory syndrome coronavirus. Infect. Disord. Drug Targets 7: 29– 41.
139. Yi, L.,, Z. Li,, K. Yuan,, X. Qu,, J. Chen,, G. Wang,, H. Zhang,, H. Luo,, L. Zhu,, P. Jiang,, L. Chen,, Y. Shen,, M. Luo,, G. Zuo,, J. Hu,, D. Duan,, Y. Nie,, X. Shi,, W. Wang,, Y. Han,, T. Li,, Y. Liu,, M. Ding,, H. Deng, and, X. Xu. 2004. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J. Virol. 78: 11334– 11339.
140. Yu, I. M.,, C. L. Gustafson,, J. Diao,, J. W. Burgner II,, Z. Li,, J. Zhang, and, J. Chen. 2005. Recombinant severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein forms a dimer through its C-terminal domain. J. Biol. Chem. 280: 23280– 23286.
141. Yuan, K.,, L. Yi,, J. Chen,, X. Qu,, T. Qing,, X. Rao,, P. Jiang,, J. Hu,, Z. Xiong,, Y. Nie,, X. Shi,, W. Wang,, C. Ling,, X. Yin,, K. Fan,, L. Lai,, M. Ding, and, H. Deng. 2004. Suppression of SARS-CoV entry by peptides corresponding to heptad regions on spike glycoprotein. Biochem. Biophys. Res. Commun. 319: 746– 752.
142. Yuan, X.,, Y. Shan,, Z. Zhao,, J. Chen, and, Y. Cong. 2005. G0/G1 arrest and apoptosis induced by SARS-CoV 3b protein in transfected cells. Virol. J. 2: 66.
143. Yuan, X.,, J. Wu,, Y. Shan,, Z. Yao,, B. Dong,, B. Chen,, Z. Zhao,, S. Wang,, J. Chen, and, Y. Cong. 2005. SARS coronavirus 7a protein blocks cell cycle progression at G0/G1 phase via the cyclin D3/pRb pathway. Virology 346: 74– 85.
144. Zhai, Y.,, F. Sun,, X. Li,, H. Pang,, X. Xu,, M. Bartlam, and, Z. Rao. 2005. Insights into SARS-CoV transcription and replication from the structure of the nsp7-nsp8 hexadecamer. Nat. Struct. Mol. Biol. 12: 980– 986.
145. Zhang, Y.,, T. Li,, L. Fu,, C. Yu,, Y. Li,, X. Xu,, Y. Wang,, H. Ning,, S. Zhang,, W. Chen,, L. A. Babiuk, and, Z. Chang. 2004. Silencing SARS-CoV Spike protein expression in cultured cells by RNA interference. FEBS Lett. 560: 141– 146.
146. Zhao, G.,, S. Q. Shi,, Y. Yang, and, J. P. Peng. 2006. M and N proteins of SARS coronavirus induce apoptosis in HPF cells. Cell Biol. Toxicol. 22: 313– 322.
147. Zhu, J.,, G. Xiao,, Y. Xu,, F. Yuan,, C. Zheng,, Y. Liu,, H. Yan,, D. K. Cole,, J. I. Bell,, Z. Rao,, P. Tien, and, G. F. Gao. 2004. Following the rule: formation of the 6-helix bundle of the fusion core from severe acute respiratory syndrome coronavirus spike protein and identification of potent peptide inhibitors. Biochem. Biophys. Res. Commun. 319: 283– 288.
148. Ziebuhr, J., and, E. J. S. 2007. The coronavirus replicase gene: special enzymes for special viruses, p. 33–63. In V. Thiel (ed.), Coronaviruses: Molecular and Cellular Biology. Caister Academic Press, Norfolk, United Kingdom.

Tables

Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus
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Citation: Barnard D, Kumaki Y. 2009. Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus, p 209-222. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch12
/content/10.1128/9781555815493.ch12.ch12tab01
Table 1.
Potential targets of inhibition of SARS-CoV by antiviral agents
Generic image for table
Table 1.

Potential targets of inhibition of SARS-CoV by antiviral agents

Citation: Barnard D, Kumaki Y. 2009. Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus, p 209-222. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch12

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