Current status of drug development against SARS CoV-2 infections
Main Article Content
Abstract
SARS CoV-2 and its associated disease Covid-19 first occurred in China at the end of 2019 and conquered the world in a storm. As of June 24, 2020, the World Health Organization listed 9,129,146 confirmed cases, accompanied by 473,797 deaths. An initial response by many countries was to lock down their economies, which helped flattening the curve at a high economic cost. The long-term solution will be vaccines to prevent infection and treatment drugs.
This minireview focuses on drugs against the virus itself. Among the drugs that interfere with the virus’ ability to attach to and invade the human cell, camostat mesylate looks promising in vitro, but clinical trials have not been completed yet. A phase II trial has been completed for recombinant human angiotension converting enzyme 2 that blocks the spike protein from binding to cellular ACE-2. Hydroxychloroquine is probably the most controversial of all drugs; after initial excitement, the Federal Drug Administration revoked the emergency use of this drug against SARS CoV-2. Among the inhibitors of the RNA dependent RNA polymerase of the virus, remdesivir, faripiravir which is already in a phase IV trial, and tenofovir will be discussed. Additional drugs included in this study are lopinavir/ritonavir that have previously been used against HIV and the antiparasitic drug ivermectin. Many of the presented drugs have previously been used for a different disease and are currently being trialed against SARS CoV-2.
Keywords:
SARS CoV-2, Covid-19, pandemic, drug development, clinical trials
Article Details
How to Cite
PRUESS, Birgit Magdalene.
Current status of drug development against SARS CoV-2 infections.
Medical Research Archives, [S.l.], v. 8, n. 8, aug. 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2203>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v8i8.2203.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3.
2. Yang Y, Peng F, Wang R, Guan K, Jiang T, Xu G, et al. The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun. 2020;109:102434.
3. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9.
4. Harcourt J, Tamin A, Lu X, Kamili S, Sakthivel SK, Murray J, et al. Severe acute respiratory syndrome coronavirus 2 from patient with coronavirus disease, United States. Emerg Infect Dis. 2020;26(6):1266-73.
5. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929-36.
6. Chen WH, Strych U, Hotez PJ, Bottazzi ME. The SARS-CoV-2 vaccine pipeline: an overview. Curr Trop Med Rep. March 2020;7:61-4.
7. Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, et al. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019;11(1):59.
8. Prüβ BM. Molecular aspects of SARS CoV-2 that impact public health. EC Microbiology. May 2020;16:59-65.
9. Guarner J. Three emerging coronaviruses in two decades. Am J Clin Pathol. 2020;153(4):420-1.
10. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
11. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5(4):562-9.
12. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-20.
13. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9(1):727-32.
14. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13(1):3-10.
15. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. May 2020;94:91-5.
16. Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med. June 2020;DOI: 10.1056/NEJMoa2020283.
17. Tsivgoulis G, Palaiodimou L, Katsanos AH, Caso V, Köhrmann M, Molina C, et al. Neurological manifestations and implications of COVID-19 pandemic. Ther Adv Neurol Disord. 2020;13:1-14.
18. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovascular research. 2020;116(6):1097-100.
19. Tobías A. Evaluation of the lockdowns for the SARS-CoV-2 epidemic in Italy and Spain after one month follow up. The Science of the total environment. 2020;725:138539.
20. Hsiang S, Allen D, Annan-Phan S, Bell K, Bolliger I, Chong T, et al. The effect of large-scale anti-contagion policies on the COVID-19 pandemic. Nature. June 2020;doi.org/10.1038/s41586-020-2404-8.
21. Krause KL, Furneaux R, Benjes P, Brimble M, Davidson T, Denny W, et al. The post-lockdown period should be used to acquire effective therapies for future resurgence in SARS-Cov-2 infections. New Zealand Med J. 2020;133(1513):107-11.
22. Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, Lin YT, et al. A Review of SARS-CoV-2 and the ongoing clinical trials. International journal of molecular sciences. 2020;21(7).
23. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234.
24. Boulware DRP, M.F.; Bangdiwala, A.S.; Pastick, M.S.; . A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Eng J Med. June 2020;DOI: 10.1056/NEJMoa2016638.
25. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering (Beijing). March 2020;doi.org/10.1016/j.eng.2020.03.007.
26. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;l382(19):1787-99.
27. Bafna K, Krug RM, Montelione GT. Structural similarity of SARS-CoV2 M(pro) and HCV NS3/4A proteases suggests new approaches for identifying existing drugs useful as COVID-19 therapeutics. ChemRxiv. 2020 DOI: 10.26434/chemrxiv.12153615.
28. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80 e8.
29. Jiang F, Yang J, Zhang Y, Dong M, Wang S, Zhang Q, et al. Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. Nat Rev Cardiol. 2014;11(7):413-26.
30. Albini A, Di Guardo G, Noonan DM, Lombardo M. The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies. Intern Emerg Med. May 2020;19:1-8.
31. Talukdar R, Tandon RK. Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. J Gastroenterol Hepatol. 2008;23(1):34-41.
32. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R, Jr., Nunneley JW, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. April 2015;116:76-84.
33. Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181(4):905-13 e7.
34. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7.
35. Chinappi M, Via A, Marcatili P, Tramontano A. On the mechanism of chloroquine resistance in Plasmodium falciparum. PloS one. 2010;5(11):e14064.
36. Koranda FC. Antimalarials. Journal of the American Academy of Dermatology. 1981;4(6):650-5.
37. Gardner G, Furst DE. Disease-modifying antirheumatic drugs. Potential effects in older patients. Drugs & aging. 1995;7(6):420-37.
38. Wu CL, Chang CC, Kor CT, Yang TH, Chiu PF, Tarng DC, et al. Hydroxychloroquine use and risk of CKD in patients with rheumatoid arthritis. Clin J Am Soc Nephrol. 2018;13(5):702-9.
39. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. August 2005;2:69.
40. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60.
41. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. March 2020:105949.
42. Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384.
43. Lenzer J. Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence. BMJ. 2020;369:m1335.
44. Koonin EV, Gorbalenya AE, Chumakov KM. Tentative identification of RNA-dependent RNA polymerases of dsRNA viruses and their relationship to positive strand RNA viral polymerases. FEBS Lett. 1989;252(1-2):42-6.
45. Kao CC, Singh P, Ecker DJ. De novo initiation of viral RNA-dependent RNA synthesis. Virology. 2001;287(2):251-60.
46. Elfiky AA. SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective. J Biomol Struct Dyn. May 2020;doi.org/10.1080/07391102.2020.1761882:1-9.
47. Yin W, Mao C, Luan X, Shen DD, Shen Q, Su H, et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science. May 2020;eabc1560.
48. Mulangu S, Dodd LE, Davey RT, Jr., Tshiani Mbaya O, Proschan M, Mukadi D, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-303.
49. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2).
50. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396):eaal3653.
51. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71.
52. Clarke MOF, J.Y.; Jordan, R.; Mackman, R.L.; Ray, A.S.; Siegel, D., Inventors. Methods for treating arenaviridae and coronaviridae virus infections. Patent US 10251904. 2019. April 09, 2019.
53. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020;382(24):2327-36.
54. Srinivas P, Sacha G, Koval C. Antivirals for COVID-19. Cleve Clin J Med. May 2020;10.3949/ccjm.87a.ccc030.
55. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449-63.
56. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100(2):446-54.
57. Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Khamduang W, Tierney C, et al. Tenofovir versus placebo to prevent perinatal transmission of hepatitis B. N Engl J Med. 2018;378(10):911-23.
58. Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016;16(1):43-52.
59. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292(2):191-201.
60. Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS (London, England). 2007;21(10):1273-81.
61. Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020;253:117592.
62. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769-802.
63. Zoufaly A, Fillekes Q, Hammerl R, Nassimi N, Jochum J, Drexler JF, et al. Prevalence and determinants of virological failure in HIV-infected children on antiretroviral therapy in rural Cameroon: a cross-sectional study. Antiviral therapy. 2013;18(5):681-90.
64. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6.
65. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875-84.
66. Burg RW, Miller BM, Baker EE, Birnbaum J, Currie SA, Hartman R, et al. Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob Agents Chemother. 1979;15(3):361-7.
67. McArthur MJ, Reinemeyer CR. Herding the U.S. cattle industry toward a paradigm shift in parasite control. Vet Parasitol. 2014;204(1-2):34-43.
68. Ottesen EA, Duke BO, Karam M, Behbehani K. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ. 1997;75(6):491-503.
69. Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. September 2018;159:55-62.
70. Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res. 2013;100(3):662-72.
71. Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 2013;99(3):301-6.
72. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851-6.
73. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. June 2020;178:104787.
74. Makenga Bof JC, Muteba D, Mansiangi P, Ilunga-Ilunga F, Coppieters Y. Analysis of severe adverse effects following community-based ivermectin treatment in the Democratic Republic of Congo. BMC pharmacology & toxicology. 2019;20(1):49.
2. Yang Y, Peng F, Wang R, Guan K, Jiang T, Xu G, et al. The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun. 2020;109:102434.
3. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9.
4. Harcourt J, Tamin A, Lu X, Kamili S, Sakthivel SK, Murray J, et al. Severe acute respiratory syndrome coronavirus 2 from patient with coronavirus disease, United States. Emerg Infect Dis. 2020;26(6):1266-73.
5. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929-36.
6. Chen WH, Strych U, Hotez PJ, Bottazzi ME. The SARS-CoV-2 vaccine pipeline: an overview. Curr Trop Med Rep. March 2020;7:61-4.
7. Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, et al. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019;11(1):59.
8. Prüβ BM. Molecular aspects of SARS CoV-2 that impact public health. EC Microbiology. May 2020;16:59-65.
9. Guarner J. Three emerging coronaviruses in two decades. Am J Clin Pathol. 2020;153(4):420-1.
10. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
11. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5(4):562-9.
12. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-20.
13. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9(1):727-32.
14. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13(1):3-10.
15. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. May 2020;94:91-5.
16. Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med. June 2020;DOI: 10.1056/NEJMoa2020283.
17. Tsivgoulis G, Palaiodimou L, Katsanos AH, Caso V, Köhrmann M, Molina C, et al. Neurological manifestations and implications of COVID-19 pandemic. Ther Adv Neurol Disord. 2020;13:1-14.
18. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovascular research. 2020;116(6):1097-100.
19. Tobías A. Evaluation of the lockdowns for the SARS-CoV-2 epidemic in Italy and Spain after one month follow up. The Science of the total environment. 2020;725:138539.
20. Hsiang S, Allen D, Annan-Phan S, Bell K, Bolliger I, Chong T, et al. The effect of large-scale anti-contagion policies on the COVID-19 pandemic. Nature. June 2020;doi.org/10.1038/s41586-020-2404-8.
21. Krause KL, Furneaux R, Benjes P, Brimble M, Davidson T, Denny W, et al. The post-lockdown period should be used to acquire effective therapies for future resurgence in SARS-Cov-2 infections. New Zealand Med J. 2020;133(1513):107-11.
22. Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, Lin YT, et al. A Review of SARS-CoV-2 and the ongoing clinical trials. International journal of molecular sciences. 2020;21(7).
23. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234.
24. Boulware DRP, M.F.; Bangdiwala, A.S.; Pastick, M.S.; . A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Eng J Med. June 2020;DOI: 10.1056/NEJMoa2016638.
25. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering (Beijing). March 2020;doi.org/10.1016/j.eng.2020.03.007.
26. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;l382(19):1787-99.
27. Bafna K, Krug RM, Montelione GT. Structural similarity of SARS-CoV2 M(pro) and HCV NS3/4A proteases suggests new approaches for identifying existing drugs useful as COVID-19 therapeutics. ChemRxiv. 2020 DOI: 10.26434/chemrxiv.12153615.
28. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80 e8.
29. Jiang F, Yang J, Zhang Y, Dong M, Wang S, Zhang Q, et al. Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. Nat Rev Cardiol. 2014;11(7):413-26.
30. Albini A, Di Guardo G, Noonan DM, Lombardo M. The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies. Intern Emerg Med. May 2020;19:1-8.
31. Talukdar R, Tandon RK. Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. J Gastroenterol Hepatol. 2008;23(1):34-41.
32. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R, Jr., Nunneley JW, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. April 2015;116:76-84.
33. Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181(4):905-13 e7.
34. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7.
35. Chinappi M, Via A, Marcatili P, Tramontano A. On the mechanism of chloroquine resistance in Plasmodium falciparum. PloS one. 2010;5(11):e14064.
36. Koranda FC. Antimalarials. Journal of the American Academy of Dermatology. 1981;4(6):650-5.
37. Gardner G, Furst DE. Disease-modifying antirheumatic drugs. Potential effects in older patients. Drugs & aging. 1995;7(6):420-37.
38. Wu CL, Chang CC, Kor CT, Yang TH, Chiu PF, Tarng DC, et al. Hydroxychloroquine use and risk of CKD in patients with rheumatoid arthritis. Clin J Am Soc Nephrol. 2018;13(5):702-9.
39. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. August 2005;2:69.
40. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60.
41. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. March 2020:105949.
42. Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384.
43. Lenzer J. Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence. BMJ. 2020;369:m1335.
44. Koonin EV, Gorbalenya AE, Chumakov KM. Tentative identification of RNA-dependent RNA polymerases of dsRNA viruses and their relationship to positive strand RNA viral polymerases. FEBS Lett. 1989;252(1-2):42-6.
45. Kao CC, Singh P, Ecker DJ. De novo initiation of viral RNA-dependent RNA synthesis. Virology. 2001;287(2):251-60.
46. Elfiky AA. SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective. J Biomol Struct Dyn. May 2020;doi.org/10.1080/07391102.2020.1761882:1-9.
47. Yin W, Mao C, Luan X, Shen DD, Shen Q, Su H, et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science. May 2020;eabc1560.
48. Mulangu S, Dodd LE, Davey RT, Jr., Tshiani Mbaya O, Proschan M, Mukadi D, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-303.
49. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2).
50. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396):eaal3653.
51. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71.
52. Clarke MOF, J.Y.; Jordan, R.; Mackman, R.L.; Ray, A.S.; Siegel, D., Inventors. Methods for treating arenaviridae and coronaviridae virus infections. Patent US 10251904. 2019. April 09, 2019.
53. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020;382(24):2327-36.
54. Srinivas P, Sacha G, Koval C. Antivirals for COVID-19. Cleve Clin J Med. May 2020;10.3949/ccjm.87a.ccc030.
55. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449-63.
56. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100(2):446-54.
57. Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Khamduang W, Tierney C, et al. Tenofovir versus placebo to prevent perinatal transmission of hepatitis B. N Engl J Med. 2018;378(10):911-23.
58. Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016;16(1):43-52.
59. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292(2):191-201.
60. Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS (London, England). 2007;21(10):1273-81.
61. Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020;253:117592.
62. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769-802.
63. Zoufaly A, Fillekes Q, Hammerl R, Nassimi N, Jochum J, Drexler JF, et al. Prevalence and determinants of virological failure in HIV-infected children on antiretroviral therapy in rural Cameroon: a cross-sectional study. Antiviral therapy. 2013;18(5):681-90.
64. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6.
65. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875-84.
66. Burg RW, Miller BM, Baker EE, Birnbaum J, Currie SA, Hartman R, et al. Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob Agents Chemother. 1979;15(3):361-7.
67. McArthur MJ, Reinemeyer CR. Herding the U.S. cattle industry toward a paradigm shift in parasite control. Vet Parasitol. 2014;204(1-2):34-43.
68. Ottesen EA, Duke BO, Karam M, Behbehani K. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ. 1997;75(6):491-503.
69. Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. September 2018;159:55-62.
70. Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res. 2013;100(3):662-72.
71. Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 2013;99(3):301-6.
72. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851-6.
73. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. June 2020;178:104787.
74. Makenga Bof JC, Muteba D, Mansiangi P, Ilunga-Ilunga F, Coppieters Y. Analysis of severe adverse effects following community-based ivermectin treatment in the Democratic Republic of Congo. BMC pharmacology & toxicology. 2019;20(1):49.