COVID-19: therapeutic approaches description and discussion

GUILHERME G. TRINDADE SAMYRA M.C. CAXITO ALESSANDRA REJANE E.O. XAVIER MAURO A.S. XAVIER FABIANA BRANDÃO About the authors

Abstract

Abstract: COVID-19 emerged in December 2019 in China, and since then, has disrupted global public health and changed economic paradigms. In dealing with the new Coronavirus, SARS-CoV-2, the world has not faced such extreme global fragility since the “Spanish flu” pandemic in 1918. Researchers globally are dedicating efforts to the search for an effective treatment for COVID-19. Drugs already used in a clinical setting for other pathologies have been tested as a new therapeutic approach against SARS-CoV-2, setting off a frenzy over the preliminary data of different studies. This work aims to compile and discuss the data published thus far. Despite the potential effects of some antivirals and antiparasitic against COVID-19, clinical studies must confirm real effectiveness. However, non-pharmacological approaches have proven to be the most efficient strategy to date.

Key words
antivirals; antiparasitic; COVID-19; SARS-CoV-2; therapeutic approaches

INTRODUCTION

The world is currently facing a pandemic caused by a virus in the Coronaviridae family, namely SARS-CoV-2, disrupting global public health and world economies. COVID-19, the disease caused by SARS-CoV-2 (WHO, 2020aWHO - WORLD HEALTH ORGANIZATION. 2020a. Naming the coronavirus disease (COVID-19) and the virus that causes it. In WHO - Naming the coronavirus disease (COVID-19) and the virus that causes it. Available at: <https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it> Accessed may/2020.
<https://www.who.int/emergencies/disease...
), is a viral infection that affects the respiratory system, resulting in respiratory syndrome. COVID-19 is considered the most serious of pandemics since 1918 when the “Spanish flu” (H1N1) (Al Hasan et al. 2020AL HASAN SM, SAULAM J, KANDA K & HIRAO T. 2020. The novel coronavirus disease (COVID-19) outbreak trends in mainland China: A joinpoint regression analysis of the outbreak data from January 10 to February 11. Bull World Health Organ [Preprint]., Zand & Wang 2020ZAND M & WANG J. 2020. Potential Mechanisms of Age Related Severity of COVID-19 Infection: Implications for Vaccine Development and Convalescent Serum Therapy. Preprint: 10.31219/osf.io/f3pze.) emerged. The search for effective treatment and vaccine is frenzied, mobilizing research groups worldwide. Currently, there are still no drugs or vaccines proven to treat or prevent infection caused by SARS-CoV-2 (CDC 2020CDC - CENTERS FOR DISEASE CONTROL AND PREVENTION 2020. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19). In Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html> Accessed may/2020.
https://www.cdc.gov/coronavirus/2019-nco...
). However, numerous studies are currently being conducted (CDC 2020CDC - CENTERS FOR DISEASE CONTROL AND PREVENTION 2020. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19). In Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html> Accessed may/2020.
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, NIH 2020NIH. 2020. Adaptive COVID-19 Treatment Trial (ACTT)—ClinicalTrials.gov. Available at: <https://clinicaltrials.gov/ct2/show/NCT04280705> Acessed may/2020.
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).

The dramatic story of COVID-19 began at the end of December 2019, when a new species of the virus from the Coronaviridae family emerged in the city of Wuhan, China (Al Hasan et al. 2020AL HASAN SM, SAULAM J, KANDA K & HIRAO T. 2020. The novel coronavirus disease (COVID-19) outbreak trends in mainland China: A joinpoint regression analysis of the outbreak data from January 10 to February 11. Bull World Health Organ [Preprint]., WHO 2020bWHO - WORLD HEALTH ORGANIZATION. 2020b. Pneumonia of unknown cause-China. Emergencies Preparedness, Response, Disease Outbreak News, World Health Organization (WHO). Available at <https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/>.
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). Initially, the outbreak demonstrated similar characteristics and symptoms to the Severe Acute Respiratory Syndrome-related Coronavirus (SARS). Initially, the World Health Organization (WHO) gave the virus the nomenclature 2019-nCoV, but it was later renamed SARS-CoV-2 by the International Committee on Viruses Taxonomy (Gorbalenya et al. 2020). Since January 21, 2020, WHO reports daily on the spread of the disease (Millán-Oñate et al. 2020MILLÁN-OÑATE J, RODRIGUEZ-MORALES AJ, CAMACHO-MORENO G, MENDOZA-RAMÍREZ H, RODRÍGUEZ-SABOGAL IA & ÁLVAREZ-MORENO C. 2020. A new emerging zoonotic virus of concern: The 2019 novel Coronavirus (COVID-19). Infectio 24(3): http://dx.doi.org/10.22354/in.v24i3.848., WHO 2020aWHO - WORLD HEALTH ORGANIZATION. 2020a. Naming the coronavirus disease (COVID-19) and the virus that causes it. In WHO - Naming the coronavirus disease (COVID-19) and the virus that causes it. Available at: <https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it> Accessed may/2020.
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)

CORONAVIRUS BIOLOGY

Coronaviridae virus family is enveloped, positive-sense single-stranded RNA included in group IV of the Baltimore classification (Gorbalenya et al. 2020GORBALENYA AE ET AL. 2020. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 5: 536-544., Arakawa & Morita 2019ARAKAWA M & MORITA E. 2019. Flavivirus Replication Organelle Biogenesis in the Endoplasmic Reticulum: Comparison with Other Single-Stranded Positive-Sense RNA Viruses. Int J Mol Sci 20(9): 2336., Reid et al. 2015REID C, AIRO A & HOBMAN T. 2015. The Virus-Host Interplay: Biogenesis of RNA Replication Complexes. In Viruses (Vol. 7).). The SARS-CoV-2 virus particles are round or oval, with a diameter of about 60–140 nm. The sequence analysis demonstrates that the novel coronavirus belongs to Betacoronavirus Lineage β, Sarbecovirus, as SARS-CoV and MERS-CoV are included (Zhu et al. 2020aZHU N ET AL. 2020. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 382(8): 727-733.).

After entering the cells, the coronavirus uses host cell protein translation machinery to produce the viral polyprotein that needs to be cleaved into effector proteins. The viral proteases coronaviral principal protease (3CLpro) and papain-like protease (PLpro) are responsible for the cleavage (Báez-Santos et al. 2015BÁEZ-SANTOS YM, ST JOHN SE & MESECAR AD. 2015. The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds. Antiviral Res 115: 21-38.). The viral genome also encodes a variety of nonstructural proteins such as RNA-dependent RNA polymerase (RdRp) (Ziebuhr et al. 2000ZIEBUHR J, SNIJDER EJ & GORBALENYA A. E. 2000. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 81(Pt 4): 853-879.).

The SARS-CoV-2 genome size varies from 29.8 kb to 29.9 kb, and share 96% identical at the whole-genome level to a bat coronavirus, and 79.6% sequence identity to SARS-CoV (Zhou et al. 2020ZHOU P ET AL. 2020a. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798): 270-273.a). Its genome structure followed the specific gene characteristics (Lu et al. 2020LU R ET AL. 2020. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 395(10224): 565-574.). The 5’ region corresponds to approximately two-thirds of the genome and holds orf1ab encoding orf1a polyproteins. The 3’ consists of genes encoding structural proteins, including surface, envelope, membrane, and nucleocapsid proteins. Besides, the SARS-CoV-2 contains six accessory proteins, encoded by ORF3a, ORF6, ORF7a, ORF7b, and ORF8 genes (Khailany et al. 2020KHAILANY RA, SAFDAR M & OZASLAN M. 2020. Genomic characterization of a novel SARS-CoV-2. Gene Rep: 100682., Li et al. 2005LI F, LI W, FARZAN M & HARRISON SC. 2005. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309(5742): 1864-1868.).

In general, viral infections follow a well-established pattern, in which viruses depend on host-cells’ biosynthetic machinery to replicate its genome and generate descending virus particles (Romero-Brey & Bartenschlager 2014ROMERO-BREY I & BARTENSCHLAGER R. 2014. Membranous replication factories induced by plus-strand RNA viruses. Viruses 6(7): 2826-2857.). Therefore, viruses are mandatory intracellular parasites (Paul & Bartenschlager 2013PAUL D & BARTENSCHLAGER R. 2013. Architecture and biogenesis of plus-strand RNA virus replication factories. World J Virol 2(2): 32-48., Romero-Brey & Bartenschlager 2016ROMERO-BREY I & BARTENSCHLAGER R. 2016. Endoplasmic Reticulum: The Favorite Intracellular Niche for Viral Replication and Assembly. Viruses 8(6).). Inside the cytoplasm, at the onset of infection, the host-cell rises to produce viral proteins instead of protein synthesis, which is interrupted by the viral proteases. This step is essential in starting the process of viral-translating genetic material (Modrow et al. 2013MODROW S, FALKE D, TRUYEN U & SCHÄTZL H. 2013. Viruses with Single-Stranded, Positive-Sense RNA Genomes. In: Modrow S, Falke D, Truyen U & Schätzl H (Eds), Molecular Virology, Springer Berlin Heidelberg, p. 185-349.). These viral lifecycle steps provide potential targets for drug therapy.

The virus infection commonly occurs between the interaction of viral surface molecules and the host-cell membrane. A host cell receptor mediates the SARS-CoV-2 entry into cells, as this hypothesis has already been tested for SARS-CoV (Xu et al. 2020XU J, ZHAO S, TENG T, ABDALLA AE, ZHU W, XIE L, WANG Y & GUO X. 2020a. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 12(2): 244., Zhou et al. 2020ZHOU P ET AL. 2020a. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798): 270-273.a). Initially, SARS-CoV was thought to enter host cells through membrane fusion (Ng et al. 2003NG ML, TAN SH, SEE EE, OOI EE & LING A. E. 2003. Early events of SARS coronavirus infection in vero cells. J Med Virol 71(3): 323-331., Qinfen et al. 2004QINFEN Z, JINMING C, XIAOJUN H, HUANYING Z, JICHENG H, LING F, KUNPENG L & JINGQIANG Z. 2004. The life cycle of SARS coronavirus in Vero E6 cells. J Med Virol 73(3): 332-337.). However, subsequent studies have shown that the SARS-CoV entry process is by receptor-mediated membrane endocytosis, and that pH also plays a role (Simmons et al. 2005SIMMONS G, GOSALIA DN, RENNEKAMP AJ, REEVES JD, DIAMOND SL & BATES P. 2005. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci USA 102(33): 11876-11881., Wang et al. 2008WANG H, YANG P, LIU K, GUO F, ZHANG Y, ZHANG G & JIANG C. 2008. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 18(2): 290-301.).

Observations have shown the SARS-CoV infects ciliated bronchial epithelial cells and type-II pneumocytes through Angiotensin-Converting Enzyme 2 (ACE2) as a receptor (Qian et al. 2013QIAN Z, TRAVANTY EA, OKO L, EDEEN K, BERGLUND A, WANG J, ITO Y, HOLMES KV & MASON RJ. 2013. Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus. Am J Respir Cell Mol Biol 48(6): 742-748.). Also, data supports that SARS-CoV uses its Spike glycoprotein (S) to bind its receptor and mediate membrane fusion and virus entry. The trimeric S protein is about 180 kDa and contains two subunits, S1 and S2, mediating attachment and membrane fusion, respectively. Nonetheless, SARS-CoV-2 spike (S) proteins share about 76% and 97% of amino acid identities with SARS-CoV and MERS, respectively (Zhou et al. 2020ZHOU P ET AL. 2020a. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798): 270-273.a). It has been shown the SARS-CoV-2 envelope spike (S) protein mediates receptor binding and membrane fusion, and it is crucial for determining host tropism and transmission capability (Lu et al. 2020LU R ET AL. 2020. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 395(10224): 565-574.).

The S protein of SARS-CoV-2 seems to be more adapted for binding to the human receptor ACE2 (Andersen et al. 2020ANDERSEN KG, RAMBAUT A, LIPKIN WI, HOLMES EC & GARRY RF. 2020. The proximal origin of SARS-CoV-2. Nat Med 26(4): 450-452.). Another host cell receptor, the type 2 transmembrane serine protease, TMPRSS2, participates in the infection process facilitating cell entry via the S protein (Hoffmann et al. 2020HOFFMANN M ET AL. 2020a. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181(2): 271-280.a). Inside the host cell, viral polyproteins are synthesized that encode for the replicase-transcriptase complex. The virus then synthesizes RNA via its RNA-dependent RNA polymerase. Structural proteins are synthesized leading to the completion of assembly and release of viral particles (Sanders et al. 2020SANDERS JM, MONOGUE ML, JODLOWSKI TZ & CUTRELL JB. 2020. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19). JAMA 323(18): 1824-1836.).

In addition to the replication process, viruses can induce strong antiviral responses in the host organism, representing a “hostility” between the virus and host to gain control over the resources of the infected cell (Nagy & Pogany 2011NAGY PD & POGANY J. 2011. The dependence of viral RNA replication on co-opted host factors. Nat Rev Microbiol 10(2): 137-149.) and when not neutralized, viruses tend to win the battle. For example, recently, studies have shown the COVID-19 disease severity triggers a “cytokine storm syndromes”, a hyperinflammatory syndrome characterized by a fulminant and fatal hypercytokinemia (Mehta et al. 2020MEHTA P, MCAULEY DF, BROWN M, SANCHEZ E, TATTERSALL RS, MANSON JJ & HLH ACROSS SPECIALITY COLLABORATION UK. 2020. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 395(10229): 1033-1034.). This “cytokine storm syndromes” is characterized by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis factor-α (Huang et al. 2020HUANG C ET AL. 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223): 497-506.). This pathophysiological phenotype of COVID-19 is an additional aggravation of infection and development of the disease.

FEASIBLE THERAPEUTIC APPROACHES

From data on other coronaviruses, such as SARS-CoV infection and the viral replication process, as well as drug tests with possible treatment results, start a “gold rush” to look for an available ligand or molecule that may affect SARS-CoV-2.

Thus, this review compiled the principal findings from the recent data. We have grouped the pivotal drugs studied at the moment with a therapeutic alternative to COVID-19. The molecular structures of these drugs are presented in figure 1. In order to make the discussion articulate, we grouped the drugs according to their mechanisms of action, or previously described function.

Figure 1
The molecular structure of the primary drugs as a therapeutic approach to COVID-19. Red: Antivirals. Green: Antiparasitic. Blue: Serine protease inhibitor. Yellow: Macrolide antibiotics.

ANTIVIRALS

Antivirals belong to the pharmacological class responsible for inhibiting the action of viruses in the body. These drugs are classified according to their action mechanisms (Hardman & Limbird 2005HARDMAN JG & LIMBIRD LE. 2005. Goodman & Gilman, As bases farmacológicas da terapêutica, tradução da 10ª edição original, Carla de Mello Vorsatz et al. Rio de Janeiro: McGram-Hill., Ison 2017ISON MG. 2017. Antiviral Treatments. Clin Chest Med 38(1): 139-153.). Standing out among these mechanisms are the following: the deactivation of virions (virus particles that appear after the viral replication process that are capable of infecting new cells), blocking the virus from binding to the cell receptor and inhibiting processes related to its replication, such as protease, integrase, and/or reverse transcriptase (Ison 2017ISON MG. 2017. Antiviral Treatments. Clin Chest Med 38(1): 139-153.).

Protease inhibitors

Widely used in the antiretroviral treatment of HIV, these inhibitors interfere with the synthesis of host-cell proteins and consequently interrupt the viral replication process. Ritonavir, Saquinavir, Fosamprenavir, and Lopinavir are examples of protease inhibitors (Mitsuyasu et al. 1998MITSUYASU RT ET AL. 1998. Activity of the soft gelatin formulation of saquinavir in combination therapy in antiretroviral-naive patients. AIDS, 12(11), F103. Available at: <https://journals.lww.com/jbjsjournal/00002030-199811000-00001.fulltext> Accessed may/2020., Tenore & Ferreira 2009TENORE SB & FERREIRA PRA. 2009. The Place of protease inhibitors in antiretroviral treatment. Braz J Infect Dis 13(5): 371-374., Lv et al. 2015LV Z, CHU Y & WANG Y. 2015. HIV protease inhibitors: A review of molecular selectivity and toxicity. HIV AIDS 7: 95-104., Midde et al. 2016MIDDE NM, PATTERS BJ, RAO P, CORY TJ & KUMAR S. 2016. Investigational protease inhibitors as antiretroviral therapies. Expert Opin Investig Drugs 25(10): 1189-1200., Pokorná et al. 2009POKORNÁ J, MACHALA L, ŘEZÁČOVÁ P & KONVALINKA J. 2009. Current and Novel Inhibitors of HIV Protease. Viruses 1(3): 1209-1239.).

Protease is a key enzyme in coronavirus polyprotein processing, and drugs such as Lopinavir and/ Ritonavir could be an option playing anti-coronavirus activity (Yavuz & Ünal 2020).

Lopinavir, Ritonavir

In 2003, after the appearance of SARS, the combination of Lopinavir and Ritonavir, two antivirals of the protease inhibitor class used in the treatment cocktail of HIV-type 1, demonstrated inhibitory activity against SARS-CoV (Chen et al. 2004CHEN F ET AL. 2004. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 31(1): 69-75., Chu et al. 2004CHU CM ET AL. 2004. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 59(3): 252-256., Wu et al. 2004WU C-Y ET AL. 2004. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci USA 101(27): 10012-10017.). The combination of Lopinavir + Ritonavir increases the plasma half-life of drugs through inhibiting cytochrome P450, which results in improved action time (Kirby et al. 2011KIRBY BJ, COLLIER AC, KHARASCH ED, WHITTINGTON D, THUMMEL KE & UNADKAT JD. 2011. Complex drug interactions of HIV protease inhibitors 1: Inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos 39(6): 1070-1078.).

Based on the findings for Lopinavir + Ritonavir against SARS-CoV, a group of researchers conducted a randomized, open, and controlled clinical trial on adult hospitalized patients with a confirmed SARS-CoV-2 infection. The data from this study was recently published in the renowned The New England Journal of Medicine. In the study, patients were divided into two groups in a 1:1 ratio. One group received treatment with Lopinavir (400 mg) + Ritonavir (100 mg) twice daily for 14 days in addition to standard treatment. The control group received only standard treatment (Cao et al. 2020CAO B ET AL. 2020. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382: 1787-1799.).

The most common adverse events observed in the Lopinavir-Ritonavir group were gastrointestinal changes. In contrast, the control group, which received standard treatment, evolved with more serious adverse events such as respiratory failure, acute renal failure, and secondary infection (Cao et al. 2020CAO B ET AL. 2020. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382: 1787-1799.).

Although the antiviral treatment did not differ significantly from the standard treatment in terms of clinical improvement (risk rate for clinical improvement 1.24, 95% confidence interval [CI], 0.90 to 1.72), the index mortality over 28 days was lower in the group treated with Lopinavir + Ritonavir (19.2% vs. 25.0%, with a 95% confidence interval, 17.3% to 5.7%) (Cao et al. 2020CAO B ET AL. 2020. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382: 1787-1799.). Another important observation of the study was that a low number of patients in the Lopinavir + Ritonavir group had severe complications (acute renal failure and secondary infection) and less need for non-invasive or invasive mechanical ventilation than the group that received only standard treatment. However, researchers are careful with these findings and suggest additional studies be conducted before affirming that the combination of these antivirals is responsible for improving the clinical picture and changing the course of the disease (Cao et al. 2020CAO B ET AL. 2020. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382: 1787-1799.).

In another clinical study, a group of Korean doctors with experience in treating patients infected by SARS-CoV-2 suggested that antiviral drugs are not recommended for use in young, healthy patients with mild symptoms and without underlying comorbid conditions (Smith & Prosser 2020SMITH T & PROSSER T. 2020. COVID-19 Drug Therapy - Potential Options. ELSEVIER, Clinical Drug Information, Clinical Solutions. Available at: <https://www.elsevier.com/__data/assets/pdf_file/0007/988648/COVID-19-Drug-Therapy_Mar-2020.pdf> Accessed may/2020.
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). In this study, the researchers recommended that the following treatment be aimed at elderly patients or those with underlying conditions and severe symptoms. The treatment combines the following medications: Lopinavir (400 mg), Ritonavir 100 mg or Chloroquine (500 mg), or Hydroxychloroquine (400 mg) (Gao et al. 2020GAO J, TIAN Z & YANG X. 2020. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 14(1): 72-73., Physicians work out treatment guidelines for coronavirus - Korea Biomedical Review 2020, Smith & Prosser 2020SMITH T & PROSSER T. 2020. COVID-19 Drug Therapy - Potential Options. ELSEVIER, Clinical Drug Information, Clinical Solutions. Available at: <https://www.elsevier.com/__data/assets/pdf_file/0007/988648/COVID-19-Drug-Therapy_Mar-2020.pdf> Accessed may/2020.
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).

Nucleotide Analogs

This class is applied as broad-spectrum antivirals and may inhibit the RNA polymerase of viruses preventing its replication (Xu et al. 2020aXU J, ZHAO S, TENG T, ABDALLA AE, ZHU W, XIE L, WANG Y & GUO X. 2020a. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 12(2): 244.). An animal model study (mice) testing Remdesivir, for example, demonstrated its inhibitory effect on Middle-East respiratory syndrome (MERS) (Agostini et al. 2018AGOSTINI ML ET AL. 2018. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio 9(2): e00221-18) and SARS-CoV (Sheahan et al. 2017SHEAHAN TP ET AL. 2017. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 9(396).).

Remdesivir

Remdesivir is an adenosine analog that is incorporated into nascent RNA chains and this step results in RNA premature termination (Warren et al. 2016WARREN TK ET AL. 2016. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531(7594): 381-385.). Remdesivir is a phosphoramidate prodrug of an adenosine C-nucleoside metabolized into its active form, GS-441524. Remdesivir delays the chain termination and blocking the proofreading function by exoribonuclease (Figure 2), an enzyme responsible for RNA degradation, by removing terminal nucleotides from both ends (5 “or 3”) (Agostini et al. 2018AGOSTINI ML ET AL. 2018. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio 9(2): e00221-18, Siegel et al. 2017SIEGEL D ET AL. 2017. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J Med Chem 60(5): 1648-1661.).

A broad-spectrum antiviral agent synthesized and developed by Gilead Sciences in 2017 as a treatment for Ebola virus infection (Siegel et al. 2017SIEGEL D ET AL. 2017. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J Med Chem 60(5): 1648-1661.). Also, Remdesivir has shown promising results for a wide variety of virus infections whose genetic material is RNA (Martinez 2020MARTINEZ MA. 2020. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother.). It has demonstrated antiviral activity against SARS and MERS (Wang et al. 2020WANG M, CAO R, ZHANG L, YANG X, LIU J, XU M, SHI Z, HU Z, ZHONG W & XIAO G. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30: 269-271.).

With promising effects previously known against Coronaviruses, a group conducted in vitro tests combining Remdesivir and Chloroquine against SARS-CoV-2. The in-vitro study evaluated the combined activity of these drugs using the Vero E6 cell model (ATC-1586). Tests were performed to measure cytotoxicity and the rate of viral infection (Wang et al. 2020WANG M, CAO R, ZHANG L, YANG X, LIU J, XU M, SHI Z, HU Z, ZHONG W & XIAO G. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30: 269-271.). The data demonstrated that the combination of these drugs potentially blocked SARS-CoV-2 infection at a low micromolar concentration (Wang et al. 2020WANG M, CAO R, ZHANG L, YANG X, LIU J, XU M, SHI Z, HU Z, ZHONG W & XIAO G. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30: 269-271.). Furthermore, the same research group claimed that Remdesivir also effectively inhibited SARS-CoV-2 infection in a human cell line (human liver cancer Huh-7 cells) (Wang et al. 2020WANG M, CAO R, ZHANG L, YANG X, LIU J, XU M, SHI Z, HU Z, ZHONG W & XIAO G. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30: 269-271.).

From these encouraging results, some groups have started clinical studies. Currently, a clinical trial testing the effectiveness of Remdesivir in patients infected with SARS-CoV-2 is being conducted in China (Smith & Prosser 2020SMITH T & PROSSER T. 2020. COVID-19 Drug Therapy - Potential Options. ELSEVIER, Clinical Drug Information, Clinical Solutions. Available at: <https://www.elsevier.com/__data/assets/pdf_file/0007/988648/COVID-19-Drug-Therapy_Mar-2020.pdf> Accessed may/2020.
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). More recently, Remdesivir was evaluated in a compassionate study in hospitalized patients diagnosed with COVID-19. The patients presented an oxygen saturation of 94% or less, breathing in the environment or with the aid of respirators. For 10 days, Remdesivir was administered in the following dosages: 200 mg on the first day and 100 mg on the next 9 days, from January 25 to March 7, 2020 (Grein et al. 2020GREIN J ET AL. 2020. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med: DOI: 10.1056/NEJMoa2007016.).

A total of 53 patients, from different regions such as North America (USA and Canada), Europe and Japan, followed in the study. Interestingly, the data showed that of the 53 hospitalized patients diagnosed with Covid-19 with severe symptoms, treated with compassionate use of Remdesivir, 36 (68%) achieved clinical improvement. However, even with promising results, the authors are cautious and claim that randomized clinical trials are needed, which are currently in progress (Grein et al. 2020GREIN J ET AL. 2020. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med: DOI: 10.1056/NEJMoa2007016.).

Figure 2
Therapeutic approaches in clinical test for COVID-19. SARS-CoV-2 model of infection and Remdesivir, Chloroquine and Hydroxychloroquine mechanisms elucidated.

Favipiravir

Favipiravir (Avigan) has been developed by Fujifilm Toyama Chemical in 2014 in Japan for the treatment of avian influenza or novel influenza resistant to neuraminidase inhibitors. Favipiravir (RNA polymerase inhibitor) is a guanine analog in the same class of the Remdesivir and as its antiviral activity similar this drug could potentially exhibit effects against SARS-CoV-2 (Furuta et al. 2017FURUTA Y, KOMENO T & NAKAMURA T. 2017. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 93(7): 449-463.).

Favipiravir initially acts as a prodrug entering cells through endocytosis, and then after phosphoribosylation and phosphorylation, it is converted into an active favipiravir ribofuranosyl phosphates (Furuta et al. 2013FURUTA Y, GOWEN BB, TAKAHASHI K, SHIRAKI K, SMEE DF & BARNARD DL. 2013. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 100(2): 446-454.). The antiviral activity is exhibited through selectively targeting the conservative catalytic domain of RNA-dependent RNA polymerase (RdRp), interrupting the nucleotide incorporation process during viral RNA replication (Furuta et al. 2017FURUTA Y, KOMENO T & NAKAMURA T. 2017. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 93(7): 449-463.). Favipiravir demonstrated 100% effectiveness in protecting mice against the Ebola virus, although its EC50 value in Vero E6 cells was high (Oestereich et al. 2014OESTEREICH L, LÜDTKE A, WURR S, RIEGER T, MUÑOZ-FONTELA C & GÜNTHER S. 2014. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res 105: 17-21.). Favipiravir has been used in the treatment of infectious diseases caused by RNA viruses such as influenza, Ebola, and norovirus (De Clercq 2019DE CLERCQ E. 2019. New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections. Chem Asian J 14(22): 3962-3968.).

OTHER MEDICATIONS

Antimalarial and antiprotozoal

Chloroquine and Hydroxychloroquine

A vigorous discussion about the use of Chloroquine and its derivative Hydroxychloroquine has raised the spirits about practical therapeutic approaches for COVID-19 treatment. Scientific evidence, while impressive, raises many questions. In this fashion, we intend to discuss and present updated data on this topic.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are aminoquinolines with known anti-inflammatory (Ornstein & Sperber 1996ORNSTEIN MH & SPERBER K. 1996. The antiinflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis. Arthritis Rheum 39(1): 157-161.) and antimalarial properties (Ben-Zvi et al. 2012BEN-ZVI I, KIVITY S, LANGEVITZ P & SHOENFELD Y. 2012. Hydroxychloroquine: From malaria to autoimmunity. Clin Rev Allergy Immunol 42(2): 145-153., Wellems & Plowe 2001WELLEMS TE & PLOWE CV. 2001. Chloroquine-resistant malaria. J Infect Dis 184(6): 770-776.), have recently emerged as “a promise” in the treatment of COVID-19 (Colson et al. 2020COLSON P, ROLAIN JM, LAGIER J-C, BROUQUI P & RAOULT D. 2020. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 55(4): 105932., Cortegiani et al. 2020CORTEGIANI A, INGOGLIA G, IPPOLITO M, GIARRATANO A & EINAV S. 2020. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care, Available at: <https://www.sciencedirect.com/science/article/pii/S0883944120303907> Accessed may/2020.
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).

Chloroquine was initially used to treat Plasmodium sp., a malaria disease agent (Aronson 2016ARONSON JK. 2016. Chloroquine and hydroxychloroquine. In Meyler’s Side Effects of Drugs, 16th ed., Elsevier, p. 253-267., Homewood et al. 1972HOMEWOOD CA, WARHURST DC, PETERS W & BAGGALEY VC. 1972. Lysosomes, pH and the anti-malarial action of chloroquine. Nature 235(5332): 50-52., Wellems & Plowe 2001WELLEMS TE & PLOWE CV. 2001. Chloroquine-resistant malaria. J Infect Dis 184(6): 770-776.). However, because of its high toxicity and the development of Plasmodium resistance to the drug (Krogstad et al. 1987KROGSTAD DJ, GLUZMAN IY, KYLE DE, ODUOLA AM, MARTIN SK, MILHOUS WK & SCHLESINGER PH. 1987. Efflux of chloroquine from Plasmodium falciparum: Mechanism of chloroquine resistance. Science 238(4831): 1283-1285.), the need to develop new molecules emerged. Hydroxychloroquine sulfate is a derivative of Chloroquine and was first synthesized in 1946 by the introduction of a hydroxyl group, and proved to be less toxic than Chloroquine (McChesney 1983MCCHESNEY EW. 1983. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med 75(1A): 11-18.) (Figure 1). HCQ is widely employed to treat autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (Rainsford et al. 2015RAINSFORD KD, PARKE AL, CLIFFORD-RASHOTTE M & KEAN WF. 2015. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 23(5): 231-269.). Its availability, proven safety record, and relatively low cost have rendered it a considerable alternative to large-scale treatment.

In humans, the effect of both Chloroquine and Hydroxychloroquine is well described. For example, it is understood that oral absorption is efficient. In animal tests, both drugs share similar standards of pharmacokinetics and bioavailability, with higher concentrations in the liver, spleen, kidney, and lung, peaking between 200–700 times greater than those of plasma (Laaksonen et al. 1974LAAKSONEN AL, KOSKIAHDE V & JUVA K. 1974. Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosus. A clinical study with determination of serum concentrations of chloroquine and hydroxychloroquine. Scand J Rheumatol 3(2): 103-108., Popert 1976POPERT AJ. 1976. Chloroquine: A review. Rheumatol Rehabil 15(3): 235-238.).

CQ and HCQ are able to modulate some cellular functions involved in immune activation such as inhibition of MHC class II expression, CD154 expression by T cells, cytokines IL-1, IFNα and TNFα, which can protect against cytokine-mediated, GMP-AMP (cGAMP) synthase (cGAS) activity, lysosomes and autophagosomes changing local pH concentrations (Schrezenmeier & Dörner 2020SCHREZENMEIER E & DÖRNER T. 2020. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nat Rev Rheumatol 16(3): 155-166.). Besides, both CQ and HCQ are weak bases known to raise the pH to reinforce the hypothesis to interfere in acidic intracellular organelles such as endosomes/lysosomes, which are essential for membrane fusion (Krogstad & Schlesinger 1987KROGSTAD DJ & SCHLESINGER PH. 1987. The basis of antimalarial action: Non-weak base effects of chloroquine on acid vesicle pH. Am J Trop Med Hyg 36(2): 213-220.). This mechanism is proposed for both drugs acting as the COVID-19 therapeutic approach.

According to these data, some studies tested CQ and HCQ against SARS-CoV-2 and have demonstrated these drugs can reasonably inhibit some virus steps of infection in a safe dosage (Liu et al. 2020LIU J, CAO R, XU M, WANG X, ZHANG H, HU H, LI Y, HU Z, ZHONG W & WANG M. 2020. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 6(1): 16.). It was proposed that CQ and HCQ could block viral entry into cells by inhibiting glycosylation of host receptors, proteolytic processing (Figure 2), and endosomal acidification (Savarino et al. 2006SAVARINO A, DI TRANI L, DONATELLI I, CAUDA R & CASSONE A. 2006. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 6(2): 67-69., Vincent et al. 2005VINCENT 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(1): 69., Zhou et al. 2020ZHOU D, DAI S-M & TONG Q. 2020b. COVID-19: A recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother: https://doi.org/10.1093/jac/dkaa114.b).

Chloroquine, in vitro, was able to inhibit SARS-CoV-2 with a half-maximal concentration (EC50) in the low micromolar range. Culture tests on Vero E6 cells with 50% and 90% effective concentrations (EC50 and EC90 values) of 1.13 μM and 6.90 μM, respectively (Wang et al. 2020WANG M, CAO R, ZHANG L, YANG X, LIU J, XU M, SHI Z, HU Z, ZHONG W & XIAO G. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30: 269-271.) were done. Also, reported mechanisms suggest a blockage of the transport of SARS-CoV-2 from endosomes to lysosomes. This step seems to be an important process for the release of the viral genome. Assuming that the maturation of the endosome may be blocked in the intermediate stages of endocytosis, this will result in the failure of the additional transport of virions to the final release site (Liu et al. 2020LIU J, CAO R, XU M, WANG X, ZHANG H, HU H, LI Y, HU Z, ZHONG W & WANG M. 2020. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 6(1): 16.).

A systematic review of the use of Chloroquine for the treatment of COVID-19 affirmed that a sufficient rationale exists for clinical use. This is in addition to preclinical evidence of efficacy and safety evidence based on the prolonged use of the drug for other diseases. However, the researchers emphasize that safety data and high-quality clinical trial data from clinical use for COVID-19 are urgently needed, which should be monitored or ethically approved for clinical trials (Cortegiani et al. 2020CORTEGIANI A, INGOGLIA G, IPPOLITO M, GIARRATANO A & EINAV S. 2020. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care, Available at: <https://www.sciencedirect.com/science/article/pii/S0883944120303907> Accessed may/2020.
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).

Since the promising in vitro data, groups have started clinical studies with CQ and HCQ in COVID-19 positive patients. A recent open-label nonrandomized French study of 36 patients (20 in the hydroxychloroquine group and 16 in the control group) reported improved virologic clearance. Oral hydroxychloroquine sulfate 200 mg was administered three times per day for ten days. The endpoint was virological clearance at day-6 post-inclusion, also secondary outcomes were virological clearance overtime during the study period, clinical follow-up (body temperature, respiratory rate, long of stay at hospital and mortality), and occurrence of side-effects. The authors tested the combination azithromycin + hydroxychloroquine, and they reported that the addition in 6 patients resulted in superior viral clearance (6/6, 100%) compared with hydroxychloroquine monotherapy (8/14, 57%) (Gautret et al. 2020GAUTRET P ET AL. 2020. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agent: 105949.).

A recent observational clinical study (Funded by the National Institutes of Health) published on May 7, in The New England Journal (Geleris et al. 2020GELERIS J ET AL. 2020. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med: DOI: 10.1056/NEJMoa2012410.) followed 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days), 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. The authors affirmed the hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death. Also, the authors conclude to be necessary randomized, controlled trials of hydroxychloroquine in patients with COVID-19 (Geleris et al. 2020GELERIS J ET AL. 2020. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med: DOI: 10.1056/NEJMoa2012410.).

A retrospective multicenter cohort study of patients from a random sample published more recently, rated the use of HCQ alone or with the interaction of Azithromycin in the metropolitan area of the state of New York - USA. In all, 1438 patients diagnosed with COVID-19, middle-aged men, aged 63, received only HCQ or both drugs, had more significant complications than patients who did not receive this therapy. The authors conclude the treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the authors also list a number of limitations of this observational study, they emphasize the need for clinical trials to provide definitive causal evidence of the effect of hydroxychloroquine and azithromycin on mortality, while also providing an opportunity to more finely control baseline patient severity and the dose and timing of drug administration (Rosenberg et al. 2020ROSENBERG ES ET AL. 2020. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA: DOI 10.1001/jama.2020.8630.).

Additionally, it is necessary to point out that even though Chloroquine and Hydroxychloroquine are relatively well-tolerated since the long time have been using for malaria treatment, studies warn of the risks. About 10% of the patients using both agents can present rare and severe adverse effects, including QTc prolongation, hypoglycemia, neuropsychiatric effects, and retinopathy (Sanders et al. 2020SANDERS JM, MONOGUE ML, JODLOWSKI TZ & CUTRELL JB. 2020. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19). JAMA 323(18): 1824-1836.).

Ultimately, a discussion on the emerging use of Chloroquine or its derivative Hydroxychloroquine is undoubtedly necessary. Scientific evidence to ensure that this treatment proposal is genuinely compelling is currently insufficient.

In Brazil, the National Health Surveillance Agency (ANVISA) first declared that although promising, no conclusive studies prove the effective use of these drugs in the treatment of COVID-19 (ANVISA 2020ANVISA - AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. 2020a. Nota Técnica sobre Cloroquina e Hidroxicloroquina. Available at: <http://portal.anvisa.gov.br/noticias/-/asset_publisher/FXrpx9qY7FbU/content/covid-19-esclarecimentos-sobre-hidroxicloroquina-e-cloroquina/219201> Accessed may/2020.
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a). More recently, ANVISA authorized a study that will apply Hydroxychloroquine in the treatment of patients with COVID-19 (ANVISA 2020ANVISA - AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. 2020b. Covid-19: Liberada pesquisa com hidroxicloroquina—Notícias. Available at: <http://portal.anvisa.gov.br/noticias/-/asset_publisher/FXrpx9qY7FbU/content/covid-19-liberada-pesquisa-com-hidroxicloroquina/219201/pop_up?_101_INSTANCE_FXrpx9qY7FbU_viewMode=print&_101_INSTANCE_FXrpx9qY7FbU_languageId=pt_BR> Accessed may/2020.
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b).

Brazilian healthy agency, ANVISA, has consent (ANVISA 2020ANVISA - AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. 2020b. Covid-19: Liberada pesquisa com hidroxicloroquina—Notícias. Available at: <http://portal.anvisa.gov.br/noticias/-/asset_publisher/FXrpx9qY7FbU/content/covid-19-liberada-pesquisa-com-hidroxicloroquina/219201/pop_up?_101_INSTANCE_FXrpx9qY7FbU_viewMode=print&_101_INSTANCE_FXrpx9qY7FbU_languageId=pt_BR> Accessed may/2020.
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b) involves two studies: a) An open, controlled study of the use of Hydroxychloroquine and Azithromycin to prevent complications in patients infected with COVID-19: a randomized and controlled study (mild to moderate cases). b) Evaluation of the safety and clinical efficacy of Hydroxychloroquine associated with Azithromycin in patients with pneumonia caused by infection with the Sars-CoV-2 virus (critically ill patients).

Antibiotic

Azithromycin

Azithromycin is an antibiotic applied for the treatment of several different types of infections caused by susceptible bacteria (Perter et al. 1992PERTER DH, FRIEDEL HA & MCTWSH D. 1992. Azithromycin a review of its antimicrobial activity, pharmacokinetic properties and clinical efficiency. Drugs 44(5): 750.). Azithromycin binds to the 50S subunit of the bacterial ribosome, inhibiting mRNA translation (Bulkley et al. 2010BULKLEY DP, INNIS CA, BLAHA G & STEITZ TA. 2010. Structure of the Thermus thermophilus 70S ribosome complexed with azithromycin. RCSB PDB doi: 10.2312/molva.20181103.
10.2312/molva.20181103...
, Tu et al. 2005TU D, BLAHA G, MOORE PB & STEITZ TA. 2005. Crystal Structure Of Azithromycin Bound To The G2099A Mutant 50S Ribosomal Subunit Of Haloarcula Marismortui. RCSB PDB: DOI 10.2210/pdb1YHQ/pdb.).

The use of Azithromycin together with other drugs has been successfully applied in the clinic for the treatment of viruses and to prevent severe respiratory tract infections for patients suffering from viral infection (Madrid et al. 2015MADRID PB ET AL. Evaluation of Ebola Virus Inhibitors for Drug Repurposing. In ACS Infectious Diseases (Vol. 1)., Retallack et al. 2016RETALLACK H ET AL. 2016. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci U S A 113(50): 14408-14413.). As discussed before, the positive data for the use of its azithromycin along with hydroxychloroquine, in a COVID-19 clinical trial have been proposed (Gautret et al. 2020GAUTRET P ET AL. 2020. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agent: 105949.). In an open-label non-randomized study in France hydroxychloroquine + azithromycin presented with the highest virologic cure rate following 6-day treatment (Gautret et al. 2020GAUTRET P ET AL. 2020. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agent: 105949.).

However, other studies affirm the data presented to date are insufficient to evaluate possible clinical benefits of azithromycin in patients with COVID-19 and repeated the experiments found patients had significant comorbidities (Molina et al. 2020MOLINA JM, DELAUGERRE C, LE GOFF J, MELA-LIMA B, PONSCARME D, GOLDWIRT L & DE CASTRO N. 2020. 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 50(4): 384.).

Nitazoxanide

Nitazoxanide (Fig. 1), an antiprotozoal, is an orally active nitrothiazolysalicylamide and antiviral prodrug that is converted rapidly to the active metabolites tizoxanide and nitazoxanide conjugates and unlike metronidazole (Rang et al. 2007RANG HP, DALE MM, RITTER JM & FLOWER RJ. 2007. Antiprotozoal drugs. In Rang & Dale’s Pharmacology., Rossignol 2016ROSSIGNOL J-F. 2016. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health 9(3): 227-230.). Similarly, nitazoxanide is also known to potentiate interferon-alfa and interferon-beta production and it has been previously shown to exhibit an in vitro activity against MERS-CoV and other coronaviruses (Rossignol 2016ROSSIGNOL J-F. 2016. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health 9(3): 227-230.).

Nitazoxanide is hypothesized as a likely therapeutic approach and could have antiviral potential against Sars-CoV-2, as it works by interfering with host-regulated pathways in viral replication, amplifying the detection of cytoplasmic RNA and Interferon type 1. Some author suggests that nitazoxanide/azithromycin combination could have a potential that should be properly tested in clinical trials including randomized controlled trials (Kelleni 2020KELLENI MT. 2020. Nitazoxanide/azithromycin combination for COVID-19: A suggested new protocol for early management. Pharmacol Res 157: 104874., Şimşek & Ünal 2020ŞIMŞEK YAVUZ S & ÜNAL S. 2020. Antiviral treatment of COVID-19. Turk J Med Sci 50(SI-1): 611-619.).

Serine protease inhibitor

Nafamostat

Nafamostat, a serine protease inhibitor that works as an anticoagulant, has demonstrated satisfactory results in inhibiting the action of MERS-CoV and has been shown to be effective against SARS-CoV-2 infection, preventing membrane fusion (Wang et al. 2020WANG M, CAO R, ZHANG L, YANG X, LIU J, XU M, SHI Z, HU Z, ZHONG W & XIAO G. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30: 269-271.).

Nafamostat mesylate inhibits TMPRSS2-dependent host cell entry of MERS-CoV (Yamamoto et al. 2016YAMAMOTO M ET AL. 2016 Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay. Antimicrobial agents and chemotherapy, v. 60, n. 11, p. 6532-6539. Available at: <http://dx.doi.org/10.1128/AAC.01043-16> Accessed may/2020.
<http://dx.doi.org/10.1128/AAC.01043-16>...
), and TMPRSS2 is responsible for cleaving and activate Sars-Cov-2 S protein. However, the use of this anticoagulant in the treatment for COVID-19 is in a clinical trial, and the exact concentration of the compound to inhibit viral replication is not yet clear. In the deficiency of this information, other serial protease inhibitors were tested to inhibit the entry of Sars-Cov-2 into the cell, such as Naphthostat mesylate, which is already used for human use in Japan and the fact that this drug inhibits the action of TMPRSS2 in the host cell for infections caused by MERS-CoV (Hoffmann et al. 2020HOFFMANN M, SCHROEDER S, KLEINE-WEBER H, MÜLLER MA, DROSTEN C & PÖHLMANN S. 2020b. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob Agents Chemother 64(6): e00754-20.b).

Nafamostat has FDA approval (unrelated to infections caused by coronavirus), and has been shown to inhibit the entry of Sars-Cov-2 mediated by protein S into the host cell with greater efficiency than Naphthostat mesylate, thus being considered the best option for the treatment of COVID-19 concerning the other serine protease inhibitors due to its higher safety and antiviral activity (Hoffmann et al. 2020HOFFMANN M, SCHROEDER S, KLEINE-WEBER H, MÜLLER MA, DROSTEN C & PÖHLMANN S. 2020b. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob Agents Chemother 64(6): e00754-20.b).

Non-pharmacological approaches

An epidemiological modeling study published at Imperial College (Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand) has been transforming the world paradigm regarding understanding adopted measures. The study demonstrates that non-pharmacological approaches can have a much more efficient impact on controlling the spread of COVID-19, thus preventing the collapse of the health system (Ferguson et al. 2020FERGUSON NM ET AL. 2020. Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand. Available at: <https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf> Accessed May/2020.
<https://www.imperial.ac.uk/media/imperi...
).

The proposed strategies to contain the population are: mitigation (which aims to reduce the demand for health care by protecting at-risk groups), and suppression (which aims to reverse the growth of the epidemic, reducing the number of cases to low levels, and maintaining this situation indefinitely) (Ferguson et al. 2020FERGUSON NM ET AL. 2020. Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand. Available at: <https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf> Accessed May/2020.
<https://www.imperial.ac.uk/media/imperi...
). According to this epidemiological modeling, without actions of containment, the number of deaths in the United States, for example, could a total of 2.2 million people.

However, the authors emphasize that it is not certain that suppression will succeed in the long term, and that no public health interventions with such disruptive effects on society have been tried before for such a long period (Ferguson et al. 2020FERGUSON NM ET AL. 2020. Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand. Available at: <https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf> Accessed May/2020.
<https://www.imperial.ac.uk/media/imperi...
).

CONCLUSIONS

There is some scientific evidence of particular drugs such as antivirals, antiparasitic, and anticoagulants as approaches for treatment Coronavirus infections (Chu et al. 2004CHU CM ET AL. 2004. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 59(3): 252-256., Martinez 2020MARTINEZ MA. 2020. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother., Wu et al. 2004WU C-Y ET AL. 2004. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci USA 101(27): 10012-10017.). Currently, more than 300 active clinical treatment trials are advancing. Unfortunately, until now, there is no evidence from randomized clinical trials with substantial therapy improves outcomes in COVID-19 patients. No clinical trial data are supporting any prophylactic therapy.

The current COVID-19 pandemic has caused hopelessness in the population, resulting in an overwhelming spread of panic and economic imbalance in affected regions (Anderson et al. 2020ANDERSON RM, HEESTERBEEK H, KLINKENBERG D & HOLLINGSWORTH TD. 2020. How will country-based mitigation measures influence the course of the COVID-19 epidemic? Lancet. DOI: https://doi.org/10.1016/S0140-6736(20)30567-5.
https://doi.org/10.1016/S0140-6736(20)30...
, Atkeson 2020ATKESON AG. 2020. What Will be the Economic Impact of COVID-19? Rough Estimates of Disease Scenarios., Ruiz Estrada 2020RUIZ ESTRADA MA. 2020. Economic Waves: The Effect of the Wuhan COVID-19 on the World Economy (2019-2020).). Thus, the population yearns for a practical therapeutic approach.

It must be emphasized that more clinical tests still need to be performed to ensure the use and effectiveness of the drugs reviewed in this work in the treatment and prevention of COVID-19 (Cao et al. 2020). The world is alarmed and confused; however, science is based on evidence generated through a rigorous methodology, which requires randomized studies for clinical application. Regrettably, these studies require time to be conducted, and results for the general population may differ from those initially evidenced in in-vitro investigations or in specific populations.

Thus, researchers, health professionals, and government representatives must discuss the best way to face this public health crisis. The most reliable way thus far adopted in various countries is preventing the virus from spreading by containing the population and enforcing mitigation. However, the appeal for the use of drugs with probable effectiveness, even with limited studies, is remarkably strong.

An important aspect to consider is that the medications currently proposed have the advantage of already being used as therapeutic options for other diseases. Consequently, these are approved for the treatment of humans, and their effects are well known. However, the results of more refined studies on safe and effective drug options will guarantee patients a truly safe treatment with the possibility of cure and/or prevention. Today, with the data thus far, this cannot be guaranteed.

ACKNOWLEGMENTS

To Professor Dr. Luiz Antonio Soares Romeiro, from the Department of Pharmacy at the University of Brasília for his support with the design of the molecular structures of the drugs discussed in this work.

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Publication Dates

  • Publication in this collection
    12 June 2020
  • Date of issue
    2020

History

  • Received
    2 Apr 2020
  • Accepted
    28 May 2020
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