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 Table of Contents  
BRIEF REPORT
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 189-192

Macrolides and COVID-19: An optimum premise


1 Department of Clinical Pharmacology, Medicine and Therapeutic, Faculty of Medical, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
2 Mitochondria, Oxidative Stress and Muscular Protection, Institute of Physiology, Faculty of Medicine, Directeur de Recherche I CNRS Emérite, Strasbourg, France

Date of Submission02-Jun-2020
Date of Acceptance04-Jul-2020
Date of Web Publication12-Sep-2020

Correspondence Address:
Prof. Hayder M Al-Kuraishy
Department of Clinical Pharmacology, Medicine and Therapeutic, Faculty of Medical, College of Medicine, Al-Mustansiriya University, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_103_20

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  Abstract 


The epidemic of coronavirus infection disease 19 (COVID-19), which started in Wuhan City, is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) which binds angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed by the lung epithelial cells. In COVID-19-induced acute respiratory distress syndrome, a hyperinflammatory syndrome with hypercytokinemia leads to acute lung injury and the development of respiratory failure. Macrolides are broad-spectrum, bacteriostatic antibiotics with significant anti-inflammatory and immunomodulatory effects. Different preclinical and clinical studies have shown that macrolides inhibit cytokine release, attenuate the inflammatory response, and improve immunoglobulin response. Azithromycin potentiates the anti-SARS-CoV-2 activity of chloroquine in COVID-19. However, azithromycin alone is effective initially in the management of COVID-19 due to its antiviral and anti-inflammatory activity. The antiviral potential of azithromycin is linked to different mechanisms, including modulation of lysosomal activity and the interaction points between SARS-CoV-2 and ACE2 receptor. Therefore, macrolides, chiefly azithromycin, are an effective drug against COVID-19 through direct antiviral effect or via the modulation of hyperinflammatory status.

Keywords: Angiotensin-converting enzyme 2, azithromycin, COVID-19, macrolides, SARS-CoV-2


How to cite this article:
Al-Kuraishy HM, Al-Naimi MS, Lungnier CM, Al-Gareeb AI. Macrolides and COVID-19: An optimum premise. Biomed Biotechnol Res J 2020;4:189-92

How to cite this URL:
Al-Kuraishy HM, Al-Naimi MS, Lungnier CM, Al-Gareeb AI. Macrolides and COVID-19: An optimum premise. Biomed Biotechnol Res J [serial online] 2020 [cited 2020 Sep 28];4:189-92. Available from: http://www.bmbtrj.org/text.asp?2020/4/3/189/294850




  Introduction Top


Coronavirus (CoV) is an enveloped positive-sense, single-strand RNA virus. CoV is the largest one among other RNA viruses from Coronaviridae family. There are three key important proteins in the structure of CoV, which are membrane protein (MP), spike protein (SP), and nucleocapsid protein (NP). These structural proteins are involved in the viral pathogenesis and regarded as targets for different experimental antiviral agents [Figure 1].[1]
Figure 1: Structure of severe acute respiratory syndrome coronavirus-2

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Previously, human CoV (HCoV-OC43) and HCoV-229E were the only known coronavirsuses, as HCoV-OC43 was isolated in 1967 from volunteers with the common cold in the United Kingdom. Analysis of genome sequences proposed that HCoV-OC43 originated and initiated from bovine, so-called bovine CoV.[2] After 2003 CoV epidemic, which caused by severe acute respiratory syndrome CoV (SARS-CoV), four types of CoV were identified, which are HCoV-NL63, HCoV-HKU1, HCoV-OC43, Middle East acute respiratory syndrome-CoV (MERS-CoV), and novel CoV infection disease 19 (COVID-19).[3] The epidemic of COVID-19 was started in Wuhan City and suspected to be originated from Huanan Seafood Market in this city, where bats are hunted and sold to the different restaurants.[4]

Most of the respiratory viruses affect bronchial ciliated cells; however, SARS-CoV-2 and SARS-CoV affect nonciliated cells via specific receptors that are angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-4 receptors, respectively.[5] In COVID-19, SARS-CoV-2 binds ACE2 receptor, which is highly expressed in the lung epithelial cells. The expression of ACE2 is increased by ACE inhibitors and angiotensin receptor blockers (ARBs), as well as by ibuprofen and thiazolidinediones, statins, and cigarette smoking.[6],[7]

Zhou et al.[8] have established that COVID-19 genome is 96% similar to that of bat CoV; hence, spike glycoprotein (S protein) and receptor binding domain of both SARS-CoV-2 and bat CoV bind ACE2, which might explain the cross-species transmission.[8]

Besides, sialic acids cap different oligosaccharides at the surface of eukaryotic cells and regarded as important receptors for all types of CoV infections. Therefore, both ACE2 and sialic acid receptors constitute potential binding sites for SARS-CoV-2 in COVID-19.[9] As well, transmembrane serine protease type II (TMPRSS2) is highly expressed on the cells that expressing ACE2 receptors, suggesting a mutual relationship for viral entry. Upon binding of SP to ACE2, the SP is subjected to different enzymatic modifications by TMPRSS2, causing structural changes in SP and ACE2 to enhance viral endocytosis. However, other trans-MPs known as NP1 and NP2 compete with TMPRSS2 for shedding of AGE2 protein (which is necessary for binding the SP of SARS-CoV-2). Viral entry induces immuno-inflammatory changes in different organs, mainly in the lung.[3],[10]

The clinical presentation of COVID-19 is mild in about 82%, and only 14.8% of them developed acute respiratory distress syndrome (ARDS); however, 5% of hospitalized patients developed septic shock or acute kidney injury.[11]

In COVID-19-induced ARDS, Mehta and McAuley have illustrated that hyperinflammatory syndrome with hypercytokinemia leads to acute lung injury and the development of respiratory failure. The hyperinflammation occurs due to the secretion of different cytokines, including tumor necrosis factor-α, monocyte chemoattract protein-1, granulocyte-colony stimulating factor, interleukins (IL-1, IL-17, and IL-6), and macrophage inflammatory protein 1-α.[12]

Therefore, IL-6 blockade (tocilizumab) is approved in China for the treatment of COVID-19 pneumonia.[13] Beside, Richardson et al.[14] have suggested that baricitinib, which is AP2-associated protein kinase-1 (AAK1) inhibitor, to be as potential therapy for COVID-19-induced ARDS. Since, AAK1 is part of Janus kinase pathway involved in the endocytosis of SARS-CoV-2 by alveolar type 2 cells (AT2), therefore AAK1 inhibitors are effective in the management of COVID-19 induced-ARDS.

Therefore, inflammatory pathways and receptor-mediated viral entry may be modulated by macrolides due to their potential anti-inflammatory and immunomodulating properties.

Macrolides including erythromycin, azithromycin, roxithromycin, and clarithromycin are broad-spectrum, bacteriostatic antibiotics with significant anti-inflammatory and immunomodulatory effects [Figure 2].[14] In general, respiratory viral infections are linked with excessive cytokine release and host immuno-inflammatory response. Different preclinical and clinical studies have shown that macrolides inhibit cytokines release, attenuate the inflammatory response, and improve immunoglobulin response.[15] Despite these findings, Arabi et al.[16] have illustrated that azithromycin or clarithromycin was ineffective in the reduction of 90-day mortality in patients with MERS caused by MERS-CoV, suggesting that macrolides' anti-inflammatory and immunomodulatory effects are not effective in the reduction of mortality rate in patients with MERS.
Figure 2: Chemical structure of macrolides. (a) Erythromycin, (b) clarithromycin, (c) azithromycin, (d) roxithromycin

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On the other hand, Huang et al.[17] found that clarithromycin was effective in the management of COVID-19 pneumonia within 6–12 days. Recently, Gautret et al.[18] found that azithromycin potentiates the anti-SARS-CoV-2 activity of chloroquine in COVID-19. However, Ariyaratne[19] disclosed that azithromycin alone is effective initially in the management of COVID-19 due to its antiviral and anti-inflammatory activity. The effect of azithromycin on SARS-CoV-2 has not yet been evaluated. Azithromycin induces antiviral responses in the epithelial cells by increasing levels of interferon and interferon-stimulated proteins and decreasing viral replication and virus release. This drug decreases expression of metalloproteinases (MMPs; molecules closely related to CD147). Both influenza A virus in the cells of asthma patients and high glucose concentrationin vitro increase CD147 expression, suggesting possible correlations within asthma, diabetes mellitus, and CD147 levels in clinical complications due to SARS-CoV-2 infection [Figure 3].[20]
Figure 3: Possible mechanisms of azithromycin against severe acute respiratory syndrome coronavirus-2

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The antiviral potential of azithromycin is linked to different mechanisms, which are:

  • Lysosomotropic activity: Azithromycin accumulates within the lysosomes and increases their pH and subsequent disruption of lysosomal membrane, which inhibits viral replication, since replication of SARS-CoV-2 depends on the intact lysosomes[21]
  • Induction the accumulation of cholesterol, phospholipids, and other neutral lipids within the lysosomes that causes dysfunctional lysosomes[22]
  • Inhibition of lysosomal protease, which is the key mediator in the replication of SARS-CoV-2[23]
  • Azithromycin blocks the interaction points between SARS-CoV-2 and ACE2 receptor.[24]


Moreover, Galvez et al.[24] have illustrated that most of the macrolide antibiotics such as azithromycin, erythromycin, and clarithromycin are promising drugs for COVID-19. Beside, other drugs such as sirolimus and rapamycin, which contain the large macrocyclic lactone, have a potential effect against COVID-19, suggesting that any drugs with this lactone might be possible future preprocessing drug touching COVID-19.[25]

What's more, different studies show that various type of macrolides has significant antiviral activities against enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), Zika virus, and pandemic influenza 2009 (A (H1N1) pdm09) virus [Table 1].[26],[27],[28],[29],[30]
Table 1: Antiviral activity of different macrolides

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Therefore, macrolides chiefly azithromycin are an effective drug against COVID-19 through direct antiviral effect or via the modulation of hyperinflammatory status.


  Conclusion Top


The antiviral potential of azithromycin is linked to different mechanisms, including modulation of lysosomal activity and the interaction points between SARS-CoV-2 and ACE2 receptor. Therefore, macrolides chiefly azithromycin are an effective drug against COVID-19 through direct antiviral effect or via the modulation of hyperinflammatory status.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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