Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture

Antimicrobial Agents and Chemotherapy

Volumn 58, Issue 8, 2014, Pages 4875-4884

  De Wilde, Adriaan H ^a   Jochmans, Dirk ^b   Posthuma, Clara C ^a   Zevenhoven Dobbe, Jessika C ^a   Van Nieuwkoop, Stefan ^c   Bestebroer, Theo M ^c   Van Den Hoogen, Bernadette G ^c   Neyts, Johan ^b   Snijder, Eric J ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^b REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

^c ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; CHLOROQUINE; CHLORPROMAZINE; LOPERAMIDE; LOPINAVIR; MOLECULAR LIBRARY;

ANIMAL; CELL LINE; CHLOROCEBUS AETHIOPS; DRUG APPROVAL; DRUG EFFECTS; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CORONAVIRUS 229E; IC50; LIVER CELL; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; MOLECULAR LIBRARY; PATHOLOGY; PHARMACOLOGY; PHYSIOLOGY; SARS CORONAVIRUS; VERO CELL LINE; VIROLOGY; VIRUS REPLICATION;

ANIMALS; ANTIVIRAL AGENTS; CELL LINE; CERCOPITHECUS AETHIOPS; CHLOROQUINE; CHLORPROMAZINE; CORONAVIRUS 229E, HUMAN; DRUG APPROVAL; HEPATOCYTES; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; INHIBITORY CONCENTRATION 50; LOPERAMIDE; LOPINAVIR; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; SARS VIRUS; SMALL MOLECULE LIBRARIES; VERO CELLS; VIRUS REPLICATION;

EID: 84905386648     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.03011-14     Document Type: Article

References (85)

1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N. Engl. J. Med. 367:1814-1820. http://dx.doi.org/10.1056/NEJMoa1211721.
2. van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus AD, Haagmans BL, Gorbalenya AE, Snijder EJ, Fouchier RA. 2012. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. mBi. 3:e00473-12. http://dx.doi.org/10. 1128/mBio.00473-12.
3. de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, Fouchier RA, Galiano M, Gorbalenya AE, Memish ZA, Perlman S, Poon LL, Snijder EJ, Stephens GM, Woo PC, Zaki AM, Zambon M, Ziebuhr J. 2013. Middle East respiratory syndrome coronavirus (MERSCoV): announcement of the Coronavirus Study Group. J. Virol. 87:7790-7792. http://dx.doi.org/10.1128/JVI.01244-13.
4. Cotten M, Watson SJ, Zumla AI, Makhdoom HQ, Palser AL, Ong SH, Al Rabeeah AA, Alhakeem RF, Assiri A, Al-Tawfiq JA, Albarrak A, Barry M, Shibl A, Alrabiah FA, Hajjar S, Balkhy HH, Flemban H, Rambaut A, Kellam P, Memish ZA. 2014. Spread, circulation, and evolution of the Middle East respiratory syndrome coronavirus. mBio 5(1):e01062-13. http://dx.doi.org/10.1128/mBio.01062-13.
5. Kupferschmidt K. 2014. Emerging diseases. Soaring MERS cases in Saudi Arabia raise alarms. Scienc. 344:457-458. http://dx.doi.org/10.1126/science.344. 6183.457.
6. Corman VM, Kallies R, Philipps H, Gopner G, Muller MA, Eckerle I, Brunink S, Drosten C, Drexler JF. 2014. Characterization of a novel betacoronavirus related to Middle East respiratory syndrome coronavirus in European hedgehogs. J. Virol. 88:717-724. http://dx.doi.org/10.1128/JVI.01600-13.
7. Haagmans BL, Al Dhahiry SH, Reusken CB, Raj VS, Galiano M, Myers R, Godeke GJ, Jonges M, Farag E, Diab A, Ghobashy H, Alhajri F, Al-Thani M, Al-Marri SA, Al Romaihi HE, Al Khal A, Bermingham A, Osterhaus AD, Alhajri MM, Koopmans MP. 2014. Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation. Lancet Infect. Dis. 14:140-145. http://dx.doi.org/10.1016/S1473-3099(13)70690-X.
8. Reusken CB, Haagmans BL, Muller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Vries LS, Corman VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, Bosch BJ, Rottier P, Osterhaus A, Gortazar-Schmidt C, Drosten C, Koopmans MP. 2013. Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect. Dis. 13:859-866. http://dx.doi.org/10.1016/S1473-3099(13)70164-6.
9. Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, Alhakeem R, Durosinloun A, Al Asmari M, Islam A, Kapoor A, Briese T, Daszak P, Al Rabeeah AA, Lipkin WI. 2013. Middle East respiratory syndrome coronavirus in bats, Saudi Arabia. Emerg. Infect. Dis. 19:1819-1823. http://dx.doi.org/10.3201/ eid1911.131172.
10. Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. 2013. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Natur. 495:251-254. http://dx.doi.org/10. 1038/nature12005.
11. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Natur. 426:450-454. http://dx.doi.org/10.1038/nature02145.
12. de Groot RJ, Cowley JA, Enjuanes L, Faaberg KS, Perlman S, Rottier PJ, Snijder EJ, Ziebuhr J, Gorbalenya AE. 2012. Order of Nidovirales, p 785-795. In King A, Adams M, Carstens E, Lefkowitz EJ (ed), Virus taxonomy, the 9th report of the International Committee on Taxonomy of Viruses. Academic Press, New York, NY.
13. Drexler JF, Corman VM, Drosten C. 2013. Ecology, evolution and classification of bat coronaviruses in the aftermath of SARS. Antiviral Res. 101:45-56. http://dx.doi.org/10.1016/j.antiviral.2013.10.013.
14. Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH, Mazet JK, Hu B, Zhang W, Peng C, Zhang YJ, Luo CM, Tan B, Wang N, Zhu Y, Crameri G, Zhang SY, Wang LF, Daszak P, Shi ZL. 2013. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Natur. 503:535-538. http://dx.doi.org/10.1038/nature12711.
15. Woo PC, Lau SK, Lam CS, Tsang AK, Hui SW, Fan RY, Martelli P, Yuen KY. 2014. Discovery of a novel bottlenose dolphin coronavirus reveals a distinct species of marine mammal coronavirus in gammacoronavirus. J. Virol. 88:1318-1331. http://dx.doi.org/10.1128/JVI.02351-13.
16. Woo PC, Lau SK, Lam CS, Lau CC, Tsang AK, Lau JH, Bai R, Teng JL, Tsang CC, Wang M, Zheng BJ, Chan KH, Yuen KY. 2012. Discovery of seven novel mammalian and avian coronaviruses in the genus Deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J. Virol. 86:3995-4008. http://dx.doi.org/10.1128/JVI.06540-11.
17. Tong TR. 2009. Drug targets in severe acute respiratory syndrome (SARS) virus and other coronavirus infections. Infect. Disord. Drug Target. 9:223-245. http://dx.doi.org/10.2174/187152609787847659.
18. Hilgenfeld R, Peiris M. 2013. From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses. Antiviral Res. 100:286-295. http://dx.doi.org/10.1016/j.antiviral.2013.08.015.
19. Tong TR. 2009. Therapies for coronaviruses. Part I of II-viral entry inhibitors. Expert Opin. Ther. Pat. 19:357-367. http://dx.doi.org/10.1517/ 13543770802609384.
20. Yang H, Xie W, Xue X, Yang K, Ma J, Liang W, Zhao Q, Zhou Z, Pei D, Ziebuhr J, Hilgenfeld R, Yuen KY, Wong L, Gao G, Chen S, Chen Z, Ma D, Bartlam M, Rao Z. 2005. Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS Biol. 3:e324. http://dx.doi.org/10.1371/journal.pbio.0030324.
21. Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S, Baker SC, Johnson ME, Mesecar AD. 2010. Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation. J. Med. Chem. 53:4968-4979. http://dx.doi.org/10.1021/jm1004489.
22. Hsu JT, Kuo CJ, Hsieh HP, Wang YC, Huang KK, Lin CP, Huang PF, Chen X, Liang PH. 2004. Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV. FEBS Lett. 574:116-120. http://dx.doi.org/10.1016/j. febslet.2004.08.015.
23. Kuo CJ, Liu HG, Lo YK, Seong CM, Lee KI, Jung YS, Liang PH. 2009. Individual and common inhibitors of coronavirus and picornavirus main proteases. FEBS Lett. 583:549-555. http://dx.doi.org/10.1016/j.febslet.2008.12.059.
24. Wu CY, Jan JT, Ma SH, Kuo CJ, Juan HF, Cheng YS, Hsu HH, Huang HC, Wu D, Brik A, Liang FS, Liu RS, Fang JM, Chen ST, Liang PH, Wong CH. 2004. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc. Natl. Acad. Sci. U. S. A. 101:10012-10017. http://dx.doi.org/10.1073/pnas. 0403596101.
25. Ratia K, Pegan S, Takayama J, Sleeman K, Coughlin M, Baliji S, Chaudhuri R, Fu W, Prabhakar BS, Johnson ME, Baker SC, Ghosh AK, Mesecar AD. 2008. A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc. Natl. Acad. Sci. U. S. A. 105:16119-16124. http://dx.doi.org/10.1073/pnas.0805240105.
26. Kilianski A, Mielech AM, Deng X, Baker SC. 2013. Assessing activity and inhibition of Middle East respiratory syndrome coronavirus papain-like and 3C-like proteases using luciferase-based biosensors. J. Virol. 87:11955-11962. http://dx.doi.org/10.1128/JVI.02105-13.
27. Graham RL, Donaldson EF, Baric RS. 2013. A decade after SARS: strategies for controlling emerging coronaviruses. Nat. Rev. Microbiol. 11:836-848. http://dx.doi.org/10.1038/nrmicro3143.
28. Wong SS, Yuen KY. 2008. The management of coronavirus infections with particular reference to SARS. J. Antimicrob. Chemother. 62:437-441. http://dx.doi.org/10.1093/jac/dkn243.
29. Hui DS. 2013. Severe acute respiratory syndrome (SARS): lessons learnt in Hong Kong. J. Thorac. Dis. 5:S122-S126. http://dx.doi.org/10.3978/j.issn.2072- 1439.2013.06.18.
30. Stockman LJ, Bellamy R, Garner P. 2006. SARS: systematic review of treatment effects. PLoS Med. 3:e343. http://dx.doi.org/10.1371/journal.pmed. 0030343.
31. Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. 2013. Inhibition of novel beta coronavirus replication by a combination of interferon-alpha2b and ribavirin. Sci. Rep. 3:1686. http://dx.doi.org/10.1038/ srep01686.
32. Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP, Brining D, Bushmaker T, Martellaro C, Baseler L, Benecke AG, Katze MG, Munster VJ, Feldmann H. 2013. Treatment with interferonalpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat. Med. 19:1313-1317. http://dx.doi.org/10.1038/nm.3362.
33. Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. 2014. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int. J. Infect. Dis. 20:42-46. http://dx.doi.org/10.1016/j.ijid.2013.12.003.
34. de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der Meer Y, Barcena M, Haagmans BL, Snijder EJ, van den Hoogen BG. 2013. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-alpha treatment. J. Gen. Virol. 94:1749-1760. http://dx.doi.org/10.1099/vir.0.052910- 0.
35. Zielecki F, Weber M, Eickmann M, Spiegelberg L, Zaki AM, Matrosovich M, Becker S, Weber F. 2013. Human cell tropism and innate immune system interactions of human respiratory coronavirus EMC compared to those of severe acute respiratory syndrome coronavirus. J. Virol. 87:5300-5304. http://dx.doi.org/10.1128/JVI.03496-12.
36. Haagmans BL, Kuiken T, Martina BE, Fouchier RA, Rimmelzwaan GF, van Amerongen G, van Riel D, de Jong T, Itamura S, Chan KH, Tashiro M, Osterhaus AD. 2004. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat. Med. 10:290-293. http://dx.doi.org/10. 1038/nm1001.
37. Paragas J, Blatt LM, Hartmann C, Huggins JW, Endy TP. 2005. Interferon alfacon1 is an inhibitor of SARS-corona virus in cell-based models. Antiviral Res. 66:99-102. http://dx.doi.org/10.1016/j.antiviral.2005.01.002.
38. Zheng B, He ML, Wong KL, Lum CT, Poon LL, Peng Y, Guan Y, Lin MC, Kung HF. 2004. Potent inhibition of SARS-associated coronavirus (SCOV) infection and replication by type I interferons (IFN-alpha/beta) but not by type II interferon (IFN-gamma). J. Interferon Cytokine Res. 24:388-390. http://dx.doi.org/10.1089/ 1079990041535610.
39. Chan RW, Chan MC, Agnihothram S, Chan LL, Kuok DI, Fong JH, Guan Y, Poon LL, Baric RS, Nicholls JM, Peiris JS. 2013. Tropism and innate immune responses of the novel human betacoronavirus lineage C virus in human ex vivo respiratory organ cultures. J. Virol. 87:6604-6614. http://dx.doi.org/10.1128/JVI.00009-13.
40. Kindler E, Jonsdottir HR, Muth D, Hamming OJ, Hartmann R, Rodriguez R, Geffers R, Fouchier RA, Drosten C, Muller MA, Dijkman R, Thiel V. 2013. Efficient replication of the novel human betacoronavirus EMC on primary human epithelium highlights its zoonotic potential. mBi. 4:e00611-12. http://dx.doi.org/10.1128/mBio.00611-12.
41. Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, Li PT, Dai J, Mok FK, Chen H, Hayden FG, Yuen KY. 2013. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J. Infect. 67:606-616. http://dx.doi.org/10.1016/j.jinf.2013.09.029.
42. Hart BJ, Dyall J, Postnikova E, Zhou H, Kindrachuk J, Johnson RF, Olinger GG, Jr, Frieman MB, Holbrook MR, Jahrling PB, Hensley L. 2014. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J. Gen. Virol. 95:571-577. http://dx.doi.org/10.1099/vir.0.061911-0.
43. de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, Thiel V, Narayanan K, Makino S, Snijder EJ, van Hemert MJ. 2011. Cyclosporin A inhibits the replication of diverse coronaviruses. J. Gen. Virol. 92:2542-2548. http://dx.doi.org/10.1099/vir.0.034983-0.
44. Pfefferle S, Schopf J, Kogl M, Friedel CC, Muller MA, Carbajo-Lozoya J, Stellberger T, von Dall'armi E, Herzog P, Kallies S, Niemeyer D, Ditt V, Kuri T, Zust R, Pumpor K, Hilgenfeld R, Schwarz F, Zimmer R, Steffen I, Weber F, Thiel V, Herrler G, Thiel HJ, Schwegmann-Wessels C, Pohlmann S, Haas J, Drosten C, von Brunn A. 2011. The SARScoronavirushost interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS Pathog. 7:e1002331. http://dx.doi.org/10.1371/journal.ppat.1002331.
45. Tanaka Y, Sato Y, Osawa S, Inoue M, Tanaka S, Sasaki T. 2012. Suppression of feline coronavirus replication in vitro by cyclosporin A. Vet. Res. 43:41. http://dx.doi.org/10.1186/1297-9716-43-41.
46. Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Zhao J, Gale MJ, Jr, Baric RS, Enjuanes L, Gallagher T, McCray PB, Jr, Perlman S. 2014. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc. Natl. Acad. Sci. U. S. A. 111:4970-4975. http://dx.doi.org/10.1073/pnas.1323279111.
47. Snijder EJ, van der MY, Zevenhoven-Dobbe J, Onderwater JJ, van der MJ, Koerten HK, Mommaas AM. 2006. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. J. Virol. 80:5927-5940. http://dx.doi.org/10.1128/JVI.02501-05.
48. Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguiere AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Muller S, Rickerts V, Sturmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW. 2003. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N. Engl. J. Med. 348:1967-1976. http://dx.doi.org/10.1056/ NEJMoa030747.
49. Cervantes-Barragan L, Zust R, Maier R, Sierro S, Janda J, Levy F, Speiser D, Romero P, Rohrlich PS, Ludewig B, Thiel V. 2010. Dendritic cell-specific antigen delivery by coronavirus vaccine vectors induces longlasting protective antiviral and antitumor immunity. mBi. 1:e00171-10. http://dx.doi.org/10.1128/ mBio.00171-10.
50. van den Worm SH, Eriksson KK, Zevenhoven JC, Weber F, Zust R, Kuri T, Dijkman R, Chang G, Siddell SG, Snijder EJ, Thiel V, Davidson AD. 2012. Reverse genetics of SARS-related coronavirus using vaccinia virus-based recombination. PLoS On. 7:e32857. http://dx.doi.org/10.1371/journal.pone.0032857.
51. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. 2004. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem. Biophys. Res. Commun. 323:264-268. http://dx.doi.org/10.1016/j.bbrc. 2004.08.085.
52. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah NG, Nichol ST. 2005. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol. J. 2:69. http://dx.doi.org/10.1186/ 1743-422X-2-69.
53. Kono M, Tatsumi K, Imai AM, Saito K, Kuriyama T, Shirasawa H. 2008. Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK. Antiviral Res. 77:150-152. http://dx.doi.org/10.1016/j.antiviral.2007.10.011.
54. Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M, Maes P. 2009. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob. Agents Chemother. 53:3416-3421. http://dx.doi.org/10.1128/AAC.01509-08.
55. Takano T, Katoh Y, Doki T, Hohdatsu T. 2013. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo. Antiviral Res. 99:100-107. http://dx.doi.org/10.1016/j.antiviral.2013.04.016.
56. Wang LH, Rothberg KG, Anderson RG. 1993. Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J. Cell Biol. 123:1107-1117. http://dx.doi.org/10.1083/jcb.123.5.1107.
57. Cotten M, Lam TT, Watson SJ, Palser AL, Petrova V, Grant P, Pybus OG, Rambaut A, Guan Y, Pillay D, Kellam P, Nastouli E. 2013. Full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus. Emerg. Infect. Dis. 19:736B-742B. http://dx.doi.org/10.3201/eid1905.130057.
58. Barnard DL, Kumaki Y. 2011. Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy. Future Virol. 6:615-631. http://dx.doi.org/10.2217/fvl.11.33.
59. Thome R, Lopes SC, Costa FT, Verinaud L. 2013. Chloroquine: modes of action of an undervalued drug. Immunol. Lett. 153:50-57. http://dx.doi.org/10. 1016/j.imlet.2013.07.004.
60. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. 2003. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect. Dis. 3:722-727. http://dx.doi.org/10.1016/S1473-3099(03)00806-5.
61. Madrid PB, Chopra S, Manger ID, Gilfillan L, Keepers TR, Shurtleff AC, Green CE, Iyer LV, Dilks HH, Davey RA, Kolokoltsov AA, Carrion R, Jr, Patterson JL, Bavari S, Panchal RG, Warren TK, Wells JB, Moos WH, Burke RL, Tanga MJ. 2013. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS On. 8:e60579. http://dx.doi.org/10.1371/journal.pone. 0060579.
62. Porotto M, Orefice G, Yokoyama CC, Mungall BA, Realubit R, Sganga ML, Aljofan M, Whitt M, Glickman F, Moscona A. 2009. Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy. J. Virol. 83:5148-5155. http://dx.doi.org/10. 1128/JVI.00164-09.
63. Mallucci L. 1966. Effect of chloroquine on lysosomes and on growth of mouse hepatitis virus (MHV-3). Virolog. 28:355-362. http://dx.doi.org/10.1016/ 0042-6822(66)90046-8.
64. Krzystyniak K, Dupuy JM. 1984. Entry of mouse hepatitis virus 3 into cells. J. Gen. Virol. 65:227-231. http://dx.doi.org/10.1099/0022-1317-65-1-227.
65. Barnard DL, Day CW, Bailey K, Heiner M, Montgomery R, Lauridsen L, Chan PK, Sidwell RW. 2006. Evaluation of immunomodulators, interferons and known in vitro SARS-coV inhibitors for inhibition of SARScoV replication in BALB/c mice. Antivir. Chem. Chemother. 17:275-284.
66. Marques MM, Costa MR, Santana Filho FS, Vieira JL, Nascimento MT, Brasil LW, Nogueira F, Silveira H, Reyes-Lecca RC, Monteiro WM, Lacerda MV, Alecrim MG. 2014. Plasmodium vivax chloroquine resistance and anemia in the Western Brazilian Amazon. Antimicrob. Agents Chemother. 58:342-347. http://dx.doi.org/ 10.1128/AAC.02279-12.
67. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA. 2012. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol. Psychiatr. 17:1206-1227. http://dx.doi.org/10.1038/mp.2012.47.
68. Pohjala L, Utt A, Varjak M, Lulla A, Merits A, Ahola T, Tammela P. 2011. Inhibitors of alphavirus entry and replication identified with a stable Chikungunya replicon cell line and virus-based assays. PLoS On. 6:e28923. http://dx.doi.org/10.1371/journal.pone.0028923.
69. Blanchard E, Belouzard S, Goueslain L, Wakita T, Dubuisson J, Wychowski C, Rouille Y. 2006. Hepatitis C virus entry depends on clathrinmediated endocytosis. J. Virol. 80:6964-6972. http://dx.doi.org/10.1128/JVI.00024-06.
70. Inoue Y, Tanaka N, Tanaka Y, Inoue S, Morita K, Zhuang M, Hattori T, Sugamura K. 2007. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. J. Virol. 81:8722-8729. http://dx.doi.org/10.1128/JVI.00253-07.
71. Chu VC, McElroy LJ, Ferguson AD, Bauman BE, Whittaker GR. 2006. Avian infectious bronchitis virus enters cells via the endocytic pathway. Adv. Exp. Med. Biol. 581:309-312. http://dx.doi.org/10.1007/978-0-387-33012-9-54.
72. Pu Y, Zhang X. 2008. Mouse hepatitis virus type 2 enters cells through a clathrin-mediated endocytic pathway independent of Eps15. J. Virol. 82:8112-8123. http://dx.doi.org/10.1128/JVI.00837-08.
73. Rivera-Calimlim L, Hershey L. 1984. Neuroleptic concentrations and clinical response. Annu. Rev. Pharmacol. Toxicol. 24:361-386. http://dx.doi.org/10.1146/annurev.pa.24.040184.002045.
74. Regnard C, Twycross R, Mihalyo M, Wilcock A. 2011. Loperamide. J. Pain Symptom Manage. 42:319-323. http://dx.doi.org/10.1016/j.jpainsymman.2011.06.001.
75. Awouters F, Niemegeers CJ, Janssen PA. 1983. Pharmacology of antidiarrheal drugs. Annu. Rev. Pharmacol. Toxicol. 23:279-301. http://dx.doi.org/10.1146/annurev.pa.23.040183.001431.
76. Lopez Aspiroz E, Santos Buelga D, Cabrera Figueroa S, Lopez Galera RM, Ribera Pascuet E, Dominguez-Gil Hurle A, Garcia Sanchez MJ. 2011. Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients. Ther. Drug Monit. 33:573-582. http://dx.doi.org/10.1097/FTD.0b013e31822d578b.
77. Caron-Debarle M, Boccara F, Lagathu C, Antoine B, Cervera P, Bastard JP, Vigouroux C, Capeau J. 2010. Adipose tissue as a target of HIV-1 antiretroviral drugs. Potential consequences on metabolic regulations. Curr. Pharm. Des. 16:3352-3360. http://dx.doi.org/10.2174/138161210793563446.
78. Tai DY. 2007. Pharmacologic treatment of SARS: current knowledge and recommendations. Ann. Acad. Med. Singapor. 36:438-443.
79. Cheng VC, Chan JF, To KK, Yuen KY. 2013. Clinical management and infection control of SARS: lessons learned. Antiviral Res. 100:407-419. http://dx.doi.org/10.1016/j.antiviral.2013.08.016.
80. Munster VJ, de Wit E, Feldmann H. 2013. Pneumonia from human coronavirus in a macaque model. N. Engl. J. Med. 368:1560-1562. http://dx.doi.org/10.1056/ NEJMc1215691.
81. Yao Y, Bao L, Deng W, Xu L, Li F, Lv Q, Yu P, Chen T, Xu Y, Zhu H, Yuan J, Gu S, Wei Q, Chen H, Yuen KY, Qin C. 2014. An animal model of MERS produced by infection of rhesus macaques with MERS coronavirus. J. Infect. Dis. 209:236-242. http://dx.doi.org/10.1093/infdis/jit590.
82. de Wit E, Rasmussen AL, Falzarano D, Bushmaker T, Feldmann F, Brining DL, Fischer ER, Martellaro C, Okumura A, Chang J, Scott D, Benecke AG, Katze MG, Feldmann H, Munster VJ. 2013. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc. Natl. Acad. Sci. U. S. A. 110:16598-16603. http://dx.doi.org/10. 1073/pnas.1310744110.
83. Coleman CM, Matthews KL, Goicochea L, Frieman MB. 2014. Wildtype and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J. Gen. Virol. 95:408-412. http://dx.doi.org/10.1099/vir. 0.060640-0.
84. Raj VS, Smits SL, Provacia LB, van den Brand JM, Wiersma L, Ouwendijk WJ, Bestebroer TM, Spronken MI, van Amerongen G, Rottier PJ, Fouchier RA, Bosch BJ, Osterhaus AD, Haagmans BL. 2014. Adenosine deaminase acts as a natural antagonist for dipeptidyl peptidase 4-mediated entry of the Middle East respiratory syndrome coronavirus. J. Virol. 88:1834-1838. http://dx.doi.org/10. 1128/JVI.02935-13.
85. Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, Johnson RF, Olinger GG, Jr, Jahrling PB, Laidlaw M, Johansen LM, Lear-Rooney CM, Glass PJ, Hensley LE, Frieman MB. 2014. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob. Agents Chemother. 58:4885-4893. http://dx.doi.org/10.1128/AAC.03036- 14.