|Year : 2020 | Volume
| Issue : 2 | Page : 29-33
Remdesivir and Dexamethasone: The Two Eligible Candidate Drugs Against Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) Infection
Yusra Binte Sikandar, Ilora Shabnam Kheya, Rashed Noor
Department of Life Sciences, School of Environment and Life Sciences, Independent University, Bangladesh (IUB), Bangladesh
|Date of Submission||06-Jul-2020|
|Date of Decision||24-Nov-2020|
|Date of Acceptance||30-Nov-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Rashed Noor
Department of Life Sciences, School of Environment and Life Sciences, Independent University, Bangladesh (IUB), Plot 16, Block B, Bashundhara R/A, Dhaka 1229
Source of Support: None, Conflict of Interest: None
Lots of research based on drug designing as well as in silico study, cell culture/animal model study, and the clinical trials are being conducted perceive the suitable therapeutic drugs and to develop vaccines in order to alleviate the ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2. Although there are still no vaccines, some potential antiviral drugs have been repurposed including remdesivir, chloroquine/hydroxychloroquine, ribavirin, favipiravir, cepharanthine, and lopinavir/ritonavir, of which remdesivir has been mostly accepted for the treatment purpose because of its multitarget actions. Besides, the immunosuppressive agent, dexamethasone, evolved with the capacity to protect the severely affected COVID-19 patients from death to some extent. The current review, thus, emphasized on both remdesivir and dexamethasone as the successful remedies for the ongoing pandemic and detected the possible mode of action of dexamethasone.
Keywords: Antiviral drugs, COVID-19 pandemic, dexamethasone, remdesivir
|How to cite this article:|
Sikandar YB, Kheya IS, Noor R. Remdesivir and Dexamethasone: The Two Eligible Candidate Drugs Against Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) Infection. Biomed Res J 2020;7:29-33
|How to cite this URL:|
Sikandar YB, Kheya IS, Noor R. Remdesivir and Dexamethasone: The Two Eligible Candidate Drugs Against Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) Infection. Biomed Res J [serial online] 2020 [cited 2021 Dec 4];7:29-33. Available from: https://www.brjnmims.org/text.asp?2020/7/2/29/305766
| Introduction|| |
It is known that lower respiratory tract infections, almost 40% caused by respiratory viruses, are solely responsible for more than 4 million deaths every year. Examples of some of the common respiratory viruses are influenza A and B, human bocavirus, human metapneumovirus, parainfluenza virus, rhinovirus, and respiratory syncytial virus. Recently, the world has witnessed another unprecedented emergence of a novel β-coronavirus (CoV), the severe acute respiratory syndrome CoV 2 (SARS-CoV-2), pandemic after the Middle East respiratory syndrome CoV outbreak in 2012 and the acute respiratory syndrome CoV (SARS-CoV) epidemic in 2002. This has been focused from the unexplained increase of pneumonia cases that has been first reported in Wuhan, China, in the last of December, 2019; and then with high transmission dynamics the COVID-19 pandemic spread all over the world so far causing 1,410,378 deaths out of 59,816,510 infected cases. Still, there is no approved vaccine to fight against the COVID-19; however, several antivirals and immunomodulatory agents have been thoroughly studied using the computational simulation models (i.e., in silico), cell culture or animal models, and the patient trials, which ultimately unraveled the potential of remdesivir, chloroquine/hydroxychloroquine, ribavirin, favipiravir, cepharanthine, and lopinavir/ritonavir to treat COVID-19 patients. Among these antivirals, remdesivir was apparently found to be one of the potential repurposed drugs; however, a contemporary study pointed toward a corticosteroid drug, dexamethasone, which imparted substantial effectiveness for the treatment of the severe COVID-19 patients requiring ventilation; and amazingly, the oral administration of dexamethasone could decrease the rate of death of the patients., The current review, therefore, discussed the possible scopes of both remdesivir and dexamethasone for curing the COVID-19 patients and specifically pointed out the targets for dexamethasone action as an immunomodulatory agent.
| Remdesivir for COVID-19 Treatment|| |
Upon entry of SARS-CoV-2 into the host cell through the viral spike (S) protein and the host angiotensin-converting enzyme 2 (ACE 2) receptor in the receptor-binding domain (RBD), the host innate immunity is triggered and the adaptive immunity (production of immunoglobulins IgM and IgG) is also activated as well., The viral entry actually results in a huge production of the pro-inflammatory cytokines and chemokines, which is often referred to as “cytokine storm,” and such spontaneous response of the innate immune system directly leads to attack of its own host system and hence leads to the onset of the acute respiratory distress syndrome (ARDS) and the major organ failure (mostly kidney and liver).,,,,, Therefore, designing of appropriate drug should have the considerations on the viral pathogenesis signaling pathway; inhibition of synthesis of viral RNA as well as the viral replication; and most importantly, inhibiting the binding of the spike (S) protein to the host ACE 2 receptor on the receptor-binding site (RBD). Remdesivir, a small molecule monophosphoramidate prodrug as well as an adenosine analog, has been found with some unique antiviral traits including the capacity to inhibit the RNA-dependent RNA polymerase (RdRp), to play a significant role in the termination of the growing RNA chain; and it can act as the nucleotide inhibitor.,,
How did remdesivir evolve as an effective antiviral drug?
Remdesivir, initially known as GS-5734 (a prodrug form of the monophosphate of a 1'-CN modified adenosine C-nucleoside hit GS-441524), first gained the interest when it was noticed to work against Ebola virus (EBOV) during its outbreak in West Africa in 2015., The antiviral screening against EBOV identified the GS-5734 as an effective inhibitor of the filoviruses (assessed through the animal model trials, i.e., using the EBOV-infected rhesus monkeys). It is worth to note that the repurposing of the drug was noticed to be effective in the patient trial too whereby significant activation of both B and T-cells was noticed by the inflammatory cytokines in the infected patients., The data from clinical trials with remdesivir revealed that it can be well tolerated by severe COVID-19 patients due to its acceptable safety profile; this drug has been recognized as the most auspicious therapeutic agent for treatment.,,, [Table 1] shows the information regarding some completed representative trials with remdesivir.
Indeed, unlike the nucleosides which were poorly cell permeable, the prodrug GS-5734 (consisting of the modified nucleosides, i.e., monophosphate, ester, and phosphoramidate) was easily permeable and was found to be metabolized, which in turn liberated the phosphorylated nucleoside within cells, together with rapid intracellular conversion to the nucleoside triphosphate, persisting in cells with its interesting trait of hindering the viral RNA polymerase, while the host mitochondrial RNA or DNA polymerases remained unaffected.
Thus, remdesivir cannot be considered to be specific only for the treatment of the COVID-19 patients; rather, it is a broad-spectrum drug, and hence it is still under clinical trial. Together with GS-5734, the GS-441524 and its S-acyl-2-thioethyl monophosphate prodrug (10-substituted 4-aza-7,9-dideazaadenosine C-nucleosides) were also found to be highly effective against EBOV infection as well as against the other RNA viruses. Such structural modification of the nucleosides thus steered to the invention of the potential broad-spectrum antiviral drug, remdesivir, going a long way to aid the treatment strategy in case of viral infections. As discussed earlier, besides the blockage of RdRp and the RNA chain truncating of the SARS-CoV-2, remdesivir can also work against the viral nonstructural protein 14 (nsp14), which has the significant role in viral replication together with the proofreading activity to avoid any mutagenesis., This is to be mentioned that while remdesivir is a potentially repurposed drug for curing the COVID-19 patients, still this broad-spectrum antiviral may impart some cons such as hepatotoxicity, constipation, nausea, diarrhea, respiratory/cardiovascular toxicity, arterial fibrillation, cardiac arrest, and renal malfunction.
| Dexamethasone: The Groundbreaking Drug for the Treatment of the COVID-19 Patients at the Severe State!|| |
Dexamethasone is a corticosteroid (30 times more active than cortisone) that has been used since the 1960s (approved by Food and Drug Administration in 1958) to reduce inflammation, the inflammatory disorders, and even cancers to some extent. Dexamethasone is also known to be a broad-spectrum immunosuppressor. In case of COVID-19 patients, dexamethasone may limit the inflammatory cytokines and can block macrophages from clearing secondary and nosocomial infections. As stated elsewhere, dexamethasone has shown the reduction of deaths in the hospitalized, severe cases of COVID-19 patients who were in the requirement of ventilator support.,
It is already known that the SARS-CoV-2 is associated with the rush of inflammatory cytokines as well as with the multiorgan malfunction, which in turn causes high morbidity and mortality due to autoimmune destruction of the lungs caused by the elevated levels of pro-inflammatory cytokines., Therefore, shielding against the viral attack must depend on the activated T-cells (especially the cytotoxic T-cells with CD + 8 marker) and specific antibodies (IgM as the first line of defense and IgG as memory). In case of COVID-19, such defending scenario is not observed; instead, the accumulation of cytokines renders the damage of lungs as stated before. Therefore, use of dexamethasone would be effective since the drug can edge the cytokines. However, the disadvantage of using this drug is that and it will also inhibit the protective function of T cells and may block the B-cells from generating IgM and IgG, and thereby leading to increased plasma viral load that may persist within a COVID-19 survivor. However, since there is still no medicine including remdesivir which can save lives in case of the sever COVID-19 situation, the drug dexamethasone has been found with the potential to reduce the death by 35%, and thus, so far, dexamethasone is considered as the “breakthrough” treatment of the severe COVID-19 patients., Another point is to consider that blocking of antibody production by dexamethasone can indirectly prevent the antibody-dependent entry of the virus, which ultimately may decrease the viral shedding. It would be feasible if the dexamethasone is administered together with the natural flavonoid luteolin because of its antiviral and anti-inflammatory properties, especially for its ability to inhibit mast cells, which are the main sources of cytokines in the lungs. However, such controversy can be resolved by an extended study about dexamethasone action including the clinical trials. Nevertheless, the ongoing clinical trials with the hospitalized patients [Table 1] revealed the desirable effectiveness of dexamethasone (i.e., lowering the mortality rate) against severe cases of COVID-19.,
Proposed model of dexamethasone action in the COVID-19 patients
As already known, that among the COVID-19 patients, inflammation is mainly triggered by the excessive production of multiple inflammatory proteins, including cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors.,, This often leads to severe asthma, and it is already known that the epithelial cells, airway smooth-muscle cells, endothelial cells, and fibroblasts are the major sources of inflammatory mediators in asthma, which is shown in [Figure 1]. The SARS-CoV-2 particles activate the epithelial cells to produce and release multiple inflammatory proteins, such as cytokines, chemokines, lipid mediators, and growth factors [Figure 1]. Dexamethasone, being a corticosteroid, is likely to prevent the release of substances in the body that cause inflammation [Figure 1]. Indeed, its usage to treat many different inflammatory conditions such as allergic disorders and skin conditions has long been known as well. At cellular level, corticosteroids may reduce the number of inflammatory cells in the airways, including eosinophils, T lymphocytes, mast cells, and dendritic cells. Dexamethasone is known to show its effect through inhibiting the recruitment of inflammatory cells into the airway by suppressing the production of chemotactic mediators and adhesion molecules. Hence, this reduces the production and expression of cytokines drastically as shown in [Figure 1]. Indeed, usage of dexamethasone appears to be worth since this drug has been successfully shown to mitigate the cytokine storm caused by SARS-CoV-2 with an evidence of shorter duration of supplemental oxygen therapy for the critically ill patients as well as a reduction in mortality by one-third in patients requiring mechanical ventilation. However, with such pros, some cons have been raised in case of influenza-induced acute lung injury, leading to a higher mortality rate., The immunosuppressant effect of dexamethasone may instigate prolonged viremia and the onset of bacterial superinfection together with other autoimmune and cardiovascular complications and the resistance to the neuromuscular blockers that are commonly employed during the mechanical ventilation.
|Figure 1: Proposed model of the possible mode of actions mediated by dexamethasone in the severe case COVID-19 patients. In case of severe COVID-19 patients, inflammation is triggered by the excessive accumulation of the multiple inflammatory proteins principally including the pro-inflammatory cytokines and chemokines, leading to severe asthma. Eventually, the severe acute respiratory syndrome-CoV-2 particles stimulate the epithelial cells which in turn are likely to be crowded with the multiple inflammatory proteins|
Click here to view
| Conclusion|| |
The current desperate situation caused by the pandemic has announced an urgent call for therapeutics. Hence, with all the previous data and evidence of the disease, researchers and scientists are trying to understand the treatment for SARS-Cov2 patients. Moreover, interpreting the basic pharmacological mechanisms and current evidence in using these agents could help physicians in selecting most appropriate plan for treatment of the infected patients. Hence, this short literature emphasizes on the antiviral drugs such as remdesivir and dexamethasone and their mode of actions along with other research evidences. Enzymes that are strictly crucial for a virus are absolutely first-class targets for antiviral drugs. For example, for SARS-CoV2, the enzyme RdRp is extremely important. Hence, remdesivir is under the spotlight as it has been very effective in vitro studies, but more implementation is necessary to firmly prove its clinical effectiveness. On the other hand, dexamethasone has been found to be extremely useful in case of the serious patients requiring the ventilation. Early treatment with intravenous dexamethasone in patients who have moderate-to-severe ARDS may attenuate the pulmonary and systemic inflammatory responses and thereby decrease both duration of mechanical ventilation and all-cause mortality. Further research along with a cascade of clinical trials are needed to check such effectiveness.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Beigel JH, Nam HH, Adams PL, Krafft A, Ince WL, El-Kamary SS, et al.
Advances in respiratory virus therapeutics - A meeting report from the 6th
isirv Antiviral Group conference. Antiviral Res 2019;167:45-67.
Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-coV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020;55:105924.
Rabaan AA, Al-Ahmed SH, Haque S, Sah R, Tiwari R, Malik YS, et al.
SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview. Infez Med 2020;28:174-84.
Noor R. Anti-viral drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggering the COVID-19 pandemic. Tzu Chi Med J 2020; DOI:10.4103/tcmj.tcmj_100_20.
Recovery Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al
. Dexamethasone in hospitalized patients with Covid-19 Preliminary report. N Engl J Med 2020;1-11:NEJMoa2021436.
Ledford H. Coronavirus breakthrough: Dexamethasone is first drug shown to save lives. Nature 2020;582:469.
Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, et al.
Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19. A C S Cent Sci 2020;6:672-83.
Sheahan TP, Sims AC, Leist SR, Schafer A, Won J, Brown AJ. et al
. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222.
Warren T, Jordan R, Lo M, Soloveva V, Ray A, Bannister R, et al
. Nucleotide prodrug GS-5734 is a broad-spectrum filovirus inhibitor that provides complete therapeutic protection against the development of ebola virus disease (EVD) in infected non-human primates. Open Forum Infect Dis 2015;2 Suppl 1:LB-2.
McElroy AK, Akondy RS, Davis CW, Ellebedy AH, Mehta AK, Kraft CS, et al.
Human ebola virus infection results in substantial immune activation. Proc Natl Acad Sci U S A 2015;112:4719-24.
Haque A, Hober D, Blondiaux J. Addressing therapeutic options for ebola virus infection in current and future outbreaks. Antimicrob Agents Chemother 2015;59:5892-902.
Wang Y, Zhou F, Zhang D, Zhao J, Du R, Hu Y. et al.
Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: Study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial. Trials 2020;21:422.
Lamb YN. Remdesivir: First approval. Drugs 2020;80:1355-63.
Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A, et al.
, Effect of remdesivir vs. standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial. JAMA 2020;324:1048-57.
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC. et al
. Remdesivir for the treatment of Covid-19 Final report. N Engl J Med 2020;383:1813-26.
Maskin LP, Olarte GL, Palizas F Jr., Velo AE, Lurbet MF, Bonelli I, et al
. High dose dexamethasone treatment for Acute Respiratory Distress Syndrome secondary to COVID-19: A structured summary of a study protocol for a randomised controlled trial. Trials 2020;21:743.
Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal 2020;10:102-8.
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:e00221-18.
Fan Q, Zhang B, Ma J, Zhang S. Safety profile of the antiviral drug remdesivir: An update. Biomed Pharmacother 2020;130:110532.
Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast. J Biol Regul Homeost Agents 2020;34:1241-3.
Finn PW, Bigby TD. Innate immunity and asthma. Proc Am Thorac Soc 2009;6:260-5.
Sikandar YB, Asaduzzaman SA, Fayz AH, Noor R. How does dexamethasone work against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? J Clin Immunol Microbiol 2020;1:1-5.
Barnes PJ. How corticosteroids control inflammation: Quintiles prize lecture 2005. Br J Pharmacol 2006;148:245-54.
Becker DE. Basic and clinical pharmacology of glucocorticosteroids. Anesth Prog 2013;60:25-31.
Mattos-Silva P, Felix NS, Silva PL, Robba C, Battaglini D, Pelosi P, et al.
Pros and cons of corticosteroid therapy for COVID-19 patients. Respir Physiol Neurobiol 2020;280:103492.
Ni YN, Chen G, Sun J, Liang BM, Liang ZA. The effect of corticosteroids on mortality of patients with influenza pneumonia: A systematic review and meta-analysis. Crit Care 2019;23:99.