Skip to main content

Present and future treatment strategies for coronavirus disease 2019

Abstract

Background

The recent pandemic of coronavirus disease 2019 (COVID-19) has resulted in many challenges to the healthcare organizations around the world. Unfortunately, until now, there are no proven effective therapeutic agents against this virus.

Main body

Several evolving studies suggest repurposing a potential list of drugs which have appropriate pharmacological and therapeutic effects to be used in treating COVID-19 cases. In the present review, we will summarize the potential drugs suggested to be repurposed to be utilized in the treatment of COVID-19 patients like lopinavir-ritonavir, ribavirin, baloxavir marboxil, favipiravir, remdesvir, umifenovir, chloroquine, hydroxychloroquine, azithromycin, corticosteroids, losartan, statins, interferons, nitric oxide, epoprostenol, tocilizumab, siltuximab, sarilumab anakinra, and ruxolitinib. In addition, we discussed the possible future therapeutic regimens based on the recent molecular and genomic discoveries.

Conclusion

This review could provide beneficial information about the potential current and future treatment strategies to treat the pandemic COVID-19 disease.

Background

In the past 20 years, many viral epidemics like the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, H1N1 influenza virus in 2009, and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 have been documented. In December 2019, an epidemic of cases having unexplained low respiratory tract infections detected in Wuhan, China, was first reported. The etiology of this disease was then attributed to a new virus that belongs to the coronavirus (CoV) family called coronavirus disease 2019 (COVID-19). It is also termed SARS-CoV-2 as it is very similar to SARS-CoV. This novel virus is very contagious and it has a very quick spread worldwide [1]. In 2020, the WHO declared COVID-19 as a pandemic disease. From December 2019 to July 2020, more than 10.4 million of COVID-19 cases have been recorded in more than 188 countries, resulting in more than 510,000 [1].

The CoVs are positive-stranded RNA viruses isolated from different animal species. They can be transmitted to humans where they can cause illness that range from common cold to more serious diseases like MERS and SARS. They belong to the Coronaviridae family, which is the largest family in the order Nidovirales. Family Coronaviridae comprises two subfamilies: subfamily Orthocoronavirinae and subfamily Torovirinae. The subfamily Orthocoronavirinae includes four genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. The viruses SARS-CoV, MERS-CoV, and COVID-19 are betacoronaviruses [2].

Coronaviruses are spherical and they are characterized by the presence of spike proteins that project from the viral surface. Due to the appearance of the viral particle under the electron microscope as a royal crown, it was named coronavirus from the Latin word corona meaning crown. CoVs are enveloped viruses and they have some structural proteins like spike (S), membrane (M), envelope (E), hemagglutinin-esterase (HE), and nucleocapsid (N) proteins. The S, M, and E, HE proteins are embedded in the envelope of the virus [1]. Nevertheless, the N protein interacts with the genetic material of the virus (RNA) forming the nucleocapsid in the core of the virus which is essential for packaging of the viral RNA into the viral particle during the viral assembly. The spike protein (S protein) is a glycosylated protein forming spikes on the surface of the virus and it mediates the entry of the virus into the cells of the host. The membrane protein (M protein) gives the virus its shape and is important together with the E protein in forming the mature envelope of the virus. The E protein also has a role in the release of the viral particles from the host cells. The HE protein is a glycoprotein which helps the virus in the attachment to the host cell surface; also it has acetyl-esterase activity [1].

There are a number of challenges in the treatment and prevention of COVID-19 that contributes to the high threat of the disease. They are summarized below. A prior good understanding of these difficulties is essential in strategizing new therapeutic alternatives.

Similar to all RNA genomes, the COVID-19 genome lacks the proofreading mechanism and so it mutates frequently. Mutations can offer the virus certain selective advantages, for instance resistance to the currently developed vaccines and antiviral drugs. In addition, mutation enables the virus to escape from the adaptive immunity of the host and increases its infectivity and virulence. Also, it can lead to greater spread of the virus either horizontally (i.e., from one individual to another within the same species) and/or vertically (i.e., crossing the host species, for instance from bats to man) [3].

A clinically relevant aspect of the pandemic COVID-19 is its ability to induce the so-called cytokine storm (CS) that consists of interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α). These pro-inflammatory mediators can provoke systemic inflammatory response syndrome, resulting in acute respiratory distress syndrome (ARDS). The pathological changes that usually occur include diffuse alveolar damage due to immunological injury and viral infection, as well as multi-organ failure including airways destruction, vascular endothelial damage, plasma leakage, and extensive microthrombus formation [4]. Pneumonia that frequently occurs in cases with COVID-19 either results as a direct consequence of the viral infection in the lung or arises due to secondary bacterial infections after the viral episode [5].

COVID-19 can be deadly to particular groups in the population, like the elderly and individuals having immune deficiency. Thus, this group is in the highest need of prophylaxis or more intensive treatments against COVID-19 [6].

The brief background discussed above clearly showed that the reliable prevention and treatment of COVID-19 represent a very critical public health need. In this review, we started with summarizing the current treatment for COVID-19. We then presented and critically reviewed the prospective future treatments for COVID-19 which are at various stages of development.

Main text

Current treatments of COVID-19

At the present time, the treatment strategies dealing with COVID-19 infection is mainly supportive, like mechanical ventilation and oxygen supplementation, and the reduction of the viral transmission in the community is the greatest weapon. Although antiviral treatments for COVID-19 have not been approved yet, several approaches have been proposed including repurpose (reposition) some therapeutics approved for other conditions for COVID-19 patients (Fig. 1). The repurposing of the antivirals includes the use of lopinavir-ritonavir, ribavirin, baloxavir marboxil, favipiravir, remdesvir, and umifenovir (arbidol). Other drugs which are not used as antivirals but have potential activity against COVID-19 include the use of chloroquine, hydroxychloroquine, azithromycin, corticosteroids, losartan, statins, interferons, nitric oxide, and epoprostenol which are examples for the repurposing strategy. Also, some agents are proposed to be used in severely ill COVID-19 patients exhibiting cytokine release syndrome (CRS) including tocilizumab, siltuximab, sarilumab anakinra, and ruxolitinib. In addition, thromboprophylaxis is suggested to be applied to all hospitalized patients with COVID-19. Passive transfer of antibodies from convalescent patient sera is another rationale that is currently used.

Fig. 1
figure 1

Targets for antiviral drugs currently available treatment for COVID-19 combined with immune modulatory agents and thromboprophylaxis

Lopinavir-ritonavir

Lopinavir is a protease inhibitor used against the human immunodeficiency virus (HIV) type 1. It is used in combination with ritonavir in order to increase its plasma half-life by inhibition of the cytochrome P450. It has an in vitro activity against SARS-CoV, MERS-CoV, and COVID-19 [7]. On the other hand, Chen et al. [8] and Cao et al. [9] did not observe any benefits from using lopinavir-ritonavir in hospitalized patients with severe COVID-19. Thus, their potential effectiveness needs to be investigated by further clinical studies.

Ribavirin

It is a guanosine analog which interferes with the replication of RNA and DNA viruses. Nevertheless, the antiviral activity of ribavirin is not only limited to its interference with polymerases but also it interferes with RNA capping that is essential to prevent RNA degradation. It presented an in vitro activity against SARS-CoV, MERS-CoV, and COVID-19 [10]. However, Tong and his colleagues [11] have reported that ribavirin did not provide a survival benefit in comparison with the control treatment (involving only supportive therapy). Its in vivo activity against SARS-CoV-2 needs further investigations.

Baloxavir marboxil

They are new inhibitors of RNA replication in influenza virus that act by targeting different protein subunits of the influenza polymerase complex. Baloxavir marboxil inhibits cap-dependent endonuclease enzyme which is involved in the initiation of mRNA synthesis [12]. Thus, these drugs are proposed to be used against SARS-CoV-2. Nevertheless, Lou et al. [13] reported that they could not prove a benefit from addition of either baloxavir marboxil in the treatment of COVID-19 patients.

Favipiravir

It is a guanine analogue and prodrug which first enters the infected host cells through endocytosis and then it is transformed into active form through phosphorylation. Its antiviral activity is demonstrated through selectively targeting the viral conservative catalytic domain of RNA-dependent RNA polymerase, leading to interruption the process of the nucleotide incorporation during the viral RNA replication. Recent in vitro and human studies have used favipiravir as an experimental agent against COVID-19 [14]. Currently, Chinese researchers have completed clinical studies on favipiravir, and it showed promising clinical efficacy in treatment of patients having COVID-19. Therefore, favipiravir will be included in the future treatment plan owing to the safety, evident efficacy, and availability of the drug [5]. Another study has revealed that patients with COVID-19 who received favipiravir had a lower mean duration of hospitalization and none of them needed mechanical ventilation [15]. On the other hand, a research group in China have not found a benefit from addition of favipiravir to the treatment protocol of COVID-19 patients [13]. They stated that the viral negativity, clinical symptoms, and laboratory tests did not provide any additional benefits to the clinical outcomes after using favipiravir in their clinical study.

Remdesvir

Remdesivir is a prodrug of an adenosine analogue having a broad antiviral spectrum. In vitro, remdesivir inhibits all human and animal coronaviruses, including COVID-19, and has shown antiviral and clinical effects in animal models of SARS-CoV and MERS-CoV. Furthermore, remdesivir has already had effective results in the USA in the fight against COVID-19 [16]. In a cohort study conducted by Grein and his colleagues [17] on hospitalized patients with severe COVID-19 disease, they noticed a clinical improvement in 68% of patients after administration of remdesvir. Yet, remdesivir needs more clinical trials to evaluate its effectiveness and safety for COVID-19 patients.

Umifenovir (arbidol)

It is an antiviral drug used in treatment of influenza infection. It can interact with the viral hemagglutinin (HA) and thus inhibiting the fusion of the viral particle to the host cell membrane. It is found that this drug inhibited crucial stages of the COVID-19 replication cycle in vitro [7]. In addition, research findings [18], conducted in Iran, showed that arbidol, significantly contributed to both clinical and laboratory improvements in COVID-19 patients.

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine (a less toxic derivative of chloroquine) are antimalarial drugs which are widely used in the treatment of rheumatic diseases and have also presented a promising activity against COVID-19. Interestingly, they inhibited the virus when the tested cells were treated with it before and/or after exposure to COVID-19, which suggests both prophylactic and therapeutic effects of these drugs. They can also affect the entry and replication of COVID-19 [19]. Nevertheless, John et al. [20] reported the potential hazard of chloroquine of induction of unwanted prolongation of QT-interval as it blocks the KCNH2-encoded HERG/Kv11.1 potassium channel leading to sudden cardiac death.

Azithromycin

It is bacteriostatic antibiotic that is widely used in treatment of many Gram-positive infections. Secondary bacterial infection pneumonia has been reported in several patients with COVID-19. Thus, azithromycin is important in treatment of pneumonia caused by bacteria [21]. In addition to its antibacterial activity, it has been revealed to have an immunomodulatory and anti-inflammatory effects thus it has a role in the reduction of the complications caused by the respiratory viral infections like SARS-CoV, MERS-CoV, and COVID-19 [22]. However, accumulating evidence advocates that azithromycin could have arrhythmia-related adverse cardiac effects via QT prolongation [23, 24] which could increase the risk of sudden cardiac death [25]. Interestingly, Gautret and his colleagues [26] proved that there is a large benefit from administration of a combination of hydroxychloroquine and azithromycin in 80 patients with COVID-19.

Corticosteroids

They are potent anti-inflammatory drugs which may prevent the occurrence of CRS in patients with COVID-19. Current animal experiments provided evidence for the effect of corticosteroids like dexamethasone, hydrocortisone, and methylprednisolone in decreasing the mortality, reduction of inflammation, attenuating the acute lung injury, reduction the period of hospitalization, decreasing the need for ventilation, and improving the survival in the severely ill patients having ARDS with doses of 15 mg/day, 400 mg/day, and 1 mg/kg/day, respectively [27]. When corticosteroids are used early in adult patients with non-critical COVID-19 pneumonia, the clinical outcomes could be worsened [28]. Although many studies were conducted to investigate the efficacy of corticosteroids in treatment of COVID-19 patients, controversy still exists as some studies have shown its benefit [29], while other studies shown no benefit [30] or a suggestion of significant harm in critically ill patients [31, 32]. So, clinical trials are urgently needed to be carried out in this aspect in order to clarify both the advantages and disadvantages of using corticosteroid therapy in patients having COVID-19.

Losartan

Losartan is an angiotensin receptor blocker that blocks angiotensin II. There has been considerable controversy over the use of angiotensin receptor blocker (ARBs) like losartan and angiotensin-converting enzyme (ACE) inhibitors (which are mainly used in treatment of elevated blood pressure) in patients with COVID-19 [33]. COVID-19 virus uses the angiotensin-converting enzyme 2 (ACE2) receptors to enter the host cells and subsequently downregulates its expression after infecting the cells leading to unopposed pro-inflammatory effects of angiotensin II [34]. Through blocking of the angiotensin II receptor, it is proposed that the utilization of losartan can lead to upregulation of the ACE2 receptor, and therefore decrease the pulmonary inflammation, fibrosis, and edema leading to a decrease in the rate and severity of the acute lung injury [33]. On the other hand, COVID-19 utilizes angiotensin-converting enzyme 2 (ACE2) as a receptor binding domain for its S protein. Thus, the increased expression of ACE2 may potentially facilitate COVID-19 infections [34]. An in silico study [35] was conducted in order to investigate the probable modulatory effect of losartan in some critical points of SARS-CoV2 replication cycle and it was elucidated that losartan has high affinity to ACE2. Bengtson and his colleagues [36] carried out a study to investigate the safety of losartan in COVID-19 patients and they reported its safety.

Statins

They are lipid-lowering drugs which have exhibited anti-inflammatory and immune-modulatory effects. Previous studies suggested the effectiveness of statin therapy in treating hospitalized influenza patients. In addition, statins have proven to have an anti-thrombotic and anticoagulant effects [37] via interference with the coagulation cascade [38] and downregulation of the clot formation by augmentation of thrombomodulin which binds to thrombin leading to activation of protein C and lowering the plasma levels of factors Va and VIIIa [39]. Thus, these findings may be encouraging to advocate statins as an adjuvant therapy for patients with COVID-19 which are highly susceptible to blood clots that could lead to mortality. However, the use of statins in COVID-19 patients needs first more studies to be conducted to ensure its efficacy.

Interferon

Type I interferons (IFNs)-α/β are broad spectrum antivirals which can exhibit both direct inhibitory effects on the viral replication and supporting the host immune response in order to clear the viral infection [40]. Recent studies have revealed that treatment with IFNs-α/β significantly decreased the duration of the detectable viruses in the upper respiratory tract as well as reduced blood levels for the inflammatory markers like Il-1, IL-6, and IL-8 [41]. Thus, these findings advocate using IFNs-α/β as a therapeutic strategy in COVID-19 cases; yet, this needs additional investigation.

Nitric oxide and epoprostenol

Both inhaled nitric oxide and inhaled epoprostenol (a naturally occurring prostaglandin) have been widely studied pulmonary vasodilator agents which are used as rescue therapy in mechanically ventilated patients with COVID-19, having severe ARDS and hypoxemia [14]. A study was carried out in the ICUs of a large academic medical center in the USA on critically ill COVID-19 patients which revealed that inhaled epoprostenol and inhaled nitric did not produce a significant increase in the oxygenation metrics. However, the study highlighted that administration of inhaled epoprostenol and inhaled nitric oxide could be considered in patients with severe respiratory failure due to COVID-19 [42].

Tocilizumab, siltuximab, and sarilumab

They are recombinant humanized monoclonal antibodies which are IL-6 receptor antagonists that block the biological activity of IL-6. They may potentially combat the release of cytokine and pro-inflammatory mediators leading to reduction in the pulmonary symptoms in severely ill patients having COVID-19 [41]. Khan and his colleagues [43] reported that tocilizumab, siltuximab, and sarilumab were associated with a lower relative risk of mortality.

Anakinra

It is a recombinant monoclonal antibody which is IL-1 receptor antagonist and is proposed to be used in severely ill patients with COVID-19 to overcome the CRS [44]. A study performed by Kooistra and his colleagues [45] on 21 severely ill COVID-19 patients treated with anakinra and they compared the clinical outcomes with a group of standard care. They observed that anakinra was effective in reduction of the clinical signs of hyperinflammation. In addition, another research group in Italy [46] reported that anakinra was effective in the management of a critical case of COVID-19.

Ruxolitinib

It is a selective inhibitor of Janus kinases (JAK) 1 and 2 which are tyrosine kinases in the host cell cytoplasm. They link cytokine signaling from the membrane receptors. As several patients with COVID-19 having severe respiratory disease due to CRS, it is hypothesized that JAK-inhibitors might have a beneficial role in treating such patients [47]. D'Alessio et al. [48] conducted a study on the effectiveness of ruxolitinib in COVID-19 patients and found that it significantly reduced the mortality without any adverse effect in the treated patients compared to controls.

Thromboprophylaxis

Individuals who are hospitalized with COVID-19 are frequently having serious respiratory failure and have elevated serum levels of D-dimer which is an initial screening indicator for venous thromboembolism (VTE). So thromboprophylaxis (prophylactic anticoagulation with anticoagulants, for instance, heparin) is an important part in the management of the critically ill patients having COVID-19 [49]. Anticoagulation Forum and American College of Cardiology recommend continuous monitoring of D-dimer, platelet count, PTT, and fibrinogen levels during administration of anticoagulants in COVID-19 patients. In addition, they recommend at least an anticoagulation course of 3 months for patients who started the anticoagulation therapy for a presumed provoked thrombus from the inflammatory state of COVID-19 disease [50].

Passive antibody transfer from convalescent patient plasma

Convalescent plasma (CP) therapy involves a recovery of blood plasma (containing neutralizing antibodies against a certain virus) from persons who have recuperated from an infection, and its administration to infected patients to improve the clinical outcomes. Patients with resolved viral infection will have high titer of polyclonal antibodies to different viral antigens of SARS-CoV-2 which will neutralize the virus [51]. Some studies were conducted by several researchers in different parts of the world on the role of CP transfusion in treatment of COVID-19 patients. Duan et al. [52] noted disappearance of viremia in 7 days and the clinical symptoms rapidly improved within 3 days after CP transfusion by severely ill patients. In addition, other researchers reported that CP transfusion for COVID-19 patients was effective and safe [53, 54]. Unfortunately, the exponential growth of the outbreak could work against this strategy as the growing number of cases would likely exceed the ability of the previous patients to provide donor sera as treatment.

Potential future therapeutic strategies for COVID-19

As there is no approved treatment for COVID-19 till the present time, the researchers all over the world are working hard in order to find an effective treatment for this pandemic disease. In an attempt to participate in this battle, we proposed some new therapeutic approaches which could be used in the future in the fight against COVID-19, some of which are being studied as future treatment options for other viruses like influenza virus, SARS-CoV, MERS-CoV, and Ebola virus.

Blocking the viral entry to the human cell

An interesting therapeutic strategy of blocking the viral entry to the human host cells was proposed by many researchers [55, 56]. Briefly, three proposed approaches would block the interaction between the S protein of SARS-CoV-2 and ACE2 receptors on the human cell surface thus, preventing the viral particles from entry which would subsequently prevent the infection. The first approach involves administration of the receptor-binding domain (RBD) of the S protein from SARS-CoV-2 virus which will bind to the ACE2 receptors leading to saturation of the available sites. In the second approach, an antibody would be administered against the ACE2 receptors to accomplish the same result of the first approach. A third approach would target the virion itself directly by using the ACE2 extracellular domain as a bait to bind to the S protein of SARS-CoV-19. Fusion of an Fc domain to ACE2 (ACE2-Fc) could allow prolonged circulation [55, 56].

Small interfering RNA

Small interfering RNA (siRNA) is a class of double-stranded RNA molecules having length ranged from 20 to 25 base pairs. siRNAs have the ability to regulate the expression of certain genes, by a phenomenon known as RNA interference (RNAi). The siRNA-based therapeutic strategies have been developed and applied for antiviral, anticancer, and genetic diseases [4]. Some previous studies revealed that siRNA-based drugs were effectively utilized against SARS-CoV and MERS-CoV by using siRNAs targeting the sequences coding for the viral RNA-dependent RNA polymerase, helicase, protease, and the nucleoprotein N. Thus, this technology should be studied as a promising treatment strategy against COVID-19 to produce better therapeutic outcomes and to reduce the viral pandemic threat.

Sphingosine mimics

Sphingosine 1-phosphate (S1P) is a lipid mediator which has diverse cellular activities. The sphingosine mimics are a group of immunosuppressants that can be used in certain infectious diseases. They can act as agonists of the sphingosine receptors leading to lymphopenia via sequestration of the lymphocytes in the lymph nodes causing immunosuppression. Recent studies have shown the therapeutic efficacy of using S1P in influenza-infected mice [57]. They noted that the intra-tracheal delivery of S1P agonist resulted in reduction in the lung injury and pro-inflammatory cytokine production. Thus, this approach of therapy could be used in the diminishing of the CRS that occurs in COVID-19 patients. Nevertheless, targeting the pro-inflammatory immune cells may not be a suitable line of treatment as it also affects the capacity of the host to clear the viral infection. Consequently, the use of S1P analogs should be utilized with caution in combination with antiviral drug in order to ensure effective clearance of the viral infection.

Nuclear factor-kappa B inhibitors

Recently, it is found that the severity of SARS-Cov-2 lies partially in its ability to activate the nuclear factor-kappa B. Nuclear factor-kappa B (NF-kB) stimulates the expression of several genes which encodes the production of cytokines leading to the CRS that frequently occurs in patients with COVID-19 [58]. Furthermore, NF-kB expresses the platelet activator receptor which increases the likelihood of thrombi formation in the peripheral capillaries. Additionally, NF-kB results in the production of GTPase (specialized for the transport of RNA polymerase II into the nucleus) that plays a great role the transcription of mRNA of SARS-CoV-2 [59]. Consequently, in order to treat patients with COVID-19, we have to control the activity of NF-Kb by using NF-kB inhibitors like Amlexanox™.

Cytokine receptors fc-fusion proteins

Recently, there are reports from Cambridge University which suggest that cytokine receptors Fc-fusion proteins can potentially serve as an antibody-like decoy to decrease the excessive levels of cytokines as a strategy of the treatment of COVID-19-infected patients [5, 60]. They utilized a new protein modification tool called QTY code, through which they can replace certain hydrophobic amino acids by other hydrophilic ones in particular cytokine receptors, including certain interleukin and interferon receptors. The QTY variant cytokine receptors display many physiological properties that are very similar to those of the native receptors without the presence of the hydrophobic segments. The receptors were then fused to the Fc region of IgG protein in order to form an antibody-like structure. These QTY code designs of the functional, water-soluble Fc-fusion as decoy therapeutic strategy to promptly remove the excessive cytokines in the hyperactive immune reactions that occur during CRS in COVID-19 seriously infected patients [60].

Regulators of the intestinal microecology

Although the main symptoms of patients having COVID-19 are respiratory symptoms like fever, cough, and dyspnea, there are less common symptoms like the headache and some gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Interestingly, it is observed that notable percentage of patients initially presented with those atypical gastrointestinal symptoms. As mentioned before, SARS-CoV-2 binds with ACE2 receptors which are highly abundant in the epithelia of both lungs and intestine of healthy individuals. Further analysis revealed that exposure of the epithelial cells of the small intestine to foreign pathogens significantly increased the expression of ACE2. Mutations in the ACE2 receptor may decrease expression of the antibacterial peptides in the cells of the intestine leading to changes in the intestinal microecology. Thus, researchers supposed that COVID-19 may have an effect on the intestinal flora by the ACE2 receptor [5]. Recent studies have presented that the use of intestinal tract microecological regulators (regulate the intestinal flora) can reduce the incidence of enteritis and respiratory-associated lung infection; thus, they can be used in the treatment of severe cases in order to maintain microbial balance in the intestine and to avoid the secondary bacterial infections [5]. Though, until now, there is no clinical evidence that the use of intestinal tract microecological regulators can have a role in the treatment of patients with COVID-19, it is still a potential treatment option, or may be used as an adjuvant therapy [61].

Drugs targeting the host interactome of SARS-CoV-2

Targeting the host genes which are necessary for the viral growth and replication is called host interactome [62] which is an attractive new model of the treatment strategies for COVID-19. This approach relies on the theory that the short-term inhibition of these host functions in order to treat an acute viral infection would not have major adverse effects. Messina et al. [63] have developed a network-based model aiming to define the molecular aspects of pathogenic phenotype in SARS-CoV-2 infection. The resulting pattern could facilitate the structure-guided pharmaceutical and diagnostic research in order to identify potential new host targets. In addition, Cava et al. [64] reported that the incorporation of drug-gene interactions in the molecular docking analysis is very helpful in finding several drugs with antiviral activity which could be used alone or in combination with other therapeutic options as new therapeutic approaches in the battle against COVID-19 pandemic disease.

Conclusion

Over the years, much research on coronaviruses has been conducted and produced various treatment strategies. Such results are likely to be applied to SARS-CoV-2 or any other evolving coronavirus in the future. With the continued hard efforts to prevent spread of SARS-CoV-2 globally, we hope that this pandemic disease will subside in a few months like SARS and MERS. Yet, this outbreak highlights the urgent need to design and produce new treatment strategies to fight against coronaviruses. Currently, our immediate action must be to achieve the infection control measures in order to prevent further worldwide transmission of COVID-19 and parallel conduction of clinical trials on the proposed therapeutic options.

Future perspective

The increased number of people infected with SARS-CoV-2 all over the world and the associated increase in the mortality rate is an important public health issue. As the number of COVID-19 cases increase, the disease control become more difficult particularly that we have no effective drugs against COVID-19. In the current review, we presented some therapeutic strategies that could be used for the current and future treatment of SARS-CoV-2 infection. Nevertheless, further research and clinical studies would elucidate the significance of the findings of the current review.

Availability of data and materials

All data and material are available upon request.

Abbreviations

COVID-19:

Coronavirus disease 2019

SARS-CoV:

Severe acute respiratory syndrome coronavirus

MERS-CoV:

Middle East respiratory syndrome coronavirus

S protein:

Spike protein

M protein:

Membrane protein

E:

Envelope

HE:

Hemagglutinin-esterase

N:

Nucleocapsid

ARDS:

Acute respiratory distress syndrome

CRS:

Cytokine release syndrome

VTE:

Venous thromboembolism

JAK:

Janus kinases

ACE:

Angiotensin-converting enzyme

ARB:

Angiotensin receptor blocker

CS:

Cytokine storm

IL-1:

Interleukin-1

IL-6:

Iinterleukin-6

IL-8:

Interleukin-8

TNF-α:

Tumor necrosis factor-alpha

RBD:

Receptor-binding domain

siRNA:

Small interfering RNA

S1P:

Sphingosine 1-phosphate

NF-kB:

Nuclear factor-kappa B

References

  1. Ashour HM, Elkhatib WF, Rahman MM, Elshabrawy HA (2020) Insights into the recent 2019 novel coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks. Path 9:186

    CAS  Google Scholar 

  2. Pal M, Berhanu G, Desalegn C, Kandi V (2020) Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): an update. Cureus 12:e7423

    PubMed  PubMed Central  Google Scholar 

  3. Pachetti M, Marini B, Benedetti F, Giudici F, Mauro E, Storici P et al (2020) Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med 18:179

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Liu C, Zhou Q, Li Y, Garner LV, Watkins SP, Carter LJ et al (2020) Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent Sci 6:315–331

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Guo G, Ye L, Pan K, Chen Y, Xing D, Yan K et al (2020) New insights of emerging SARS-CoV-2: epidemiology, etiology, clinical features, clinical treatment, and prevention. Front Cell Develop Biol 8:410–425

    Article  Google Scholar 

  6. Jayawardena R, Sooriyaarachchi P, Chourdakis M, Jeewandara C, Ranasinghe P (2020) Enhancing immunity in viral infections, with special emphasis on COVID-19: a review. Diabetol Metab Syndr 14:367–382

    Article  Google Scholar 

  7. Lima WG, Brito JM, Overhage J, Nizer W (2020) The potential of drug repositioning as a short-term strategy for the control and treatment of COVID-19 (SARS-CoV-2): a systematic review. Arch Virol 2:1

    Google Scholar 

  8. Chen Y, Wang A, Yi B, Ding K, Wang H, Wang J et al (2020) The epidemiological characteristics of infection in close contacts of COVID-19 in Ningbo city. Chin J Epidemiol 41:20–29

    Google Scholar 

  9. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al (2020) A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 7:1787–1799

    Article  Google Scholar 

  10. Khalili JS, Zhu H, Mak N, Yan Y, Zhu Y (2020) Novel coronavirus treatment with ribavirin: groundwork for an evaluation concerning COVID-19. J Med Virol 92:740–746

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. Tong S, Su Y, Yu Y, Wu C, Chen J, Wang S et al (2020) Ribavirin therapy for severe COVID-19: a retrospective cohort study. Int J Antimicrob Agents 56:106–114

    Article  CAS  Google Scholar 

  12. Lou Y, Liu L, Qiu Y (2020) Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled. Trial Med Rxiv 1:4

    Google Scholar 

  13. Lou Y, Liu L, Yao H, Hu X, Su J, Xu K et al (2021) Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial. Eur J Pharm Sci 157:105631

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. Wu R, Wang L, Kuo HD, Shannar A, Peter R, Chou PJ et al (2020) An update on current therapeutic drugs treating COVID-19. Curr Pharm Rep 1:15

    Google Scholar 

  15. Dabbous HM, Abd-Elsalam S, El-Sayed MH, Sherief AF, Ebeid FF, Abd El Ghafar MS et al (2021) Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study. Arch Virol 166:949–954

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H et al (2020) First case of 2019 novel coronavirus in the United States. N Engl J Med 382:929–936

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A et al (2020) Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 11:2327–2336

    Article  Google Scholar 

  18. Nojomi M, Yassin Z, Keyvani H, Makiani J, Roham M, Laali A et al (2020) Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial. BMC Infect Dis 20:954

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Schrezenmeier E, Dörner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16:155–166

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. Joh RG, Peter AN, Paul AF, Michael JA (2020) Urgent guidance for navigating and circumventing the QTC-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). JMCP Mayo Clin Proc 3:24–36

    Google Scholar 

  21. Sultana J, Cutroneo PM, Crisafulli S, Puglisi G, Caramori G, Trifirò G (2020) Azithromycin in COVID-19 patients: pharmacological mechanism, clinical evidence and prescribing guidelines. Drug Saf 43:691–698

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Pania A, Lauriola M, Romandinia A, Scaglione F (2020) Macrolides and viral infections: focus on azithromycin in COVID-19 pathology. Int J Antimicrob Agents 10:6053

    Google Scholar 

  23. Russo V, Puzio G, Siniscalchi N (2006) Azithromycin-induced QT prolongation in elderly patient. Acta Biomed 77:30–32

    PubMed  PubMed Central  Google Scholar 

  24. Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD (2007) Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol 18:243–246

    PubMed  Article  PubMed Central  Google Scholar 

  25. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM (2012) Azithromycin and the risk of cardiovascular death. N Engl J Med 366:1881–1890

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J et al (2020) Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med Infect Dis 34:101663

    PubMed  PubMed Central  Article  Google Scholar 

  27. Meduri GU, Bridges L, Shih MC, Marik PE, Siemieniuk RAC, Kocak M (2016) Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med 42:829–840

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. Li Q, Li W, Jin Y, Xu W, Huang C, Li L et al (2020) Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Ther 9:823–836

    PubMed  Article  PubMed Central  Google Scholar 

  29. Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA et al (2020) Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med 8:267–276

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. Wang D, Hu B, Hu C, Zhu F, Peng Z (2020) Clinical characteristics of 138 hospitalized patients with 2019 novel corona virus–infected pneumonia in Wuhan, China. J Am Med Assoc 323:1061–1069

    CAS  Article  Google Scholar 

  31. Ling Y, Xu S, Lin Y, Zhu Z (2020) Persistence and clearance of viral RNA in 2019 novel corona virus disease rehabilitation patients Chinese. Med J 133:9

    Article  Google Scholar 

  32. Veronese N, Demurtas J, Yang L, Tonelli R, Barbagallo M, Lopalco P et al (2020) Use of corticosteroids in coronavirus disease 2019 pneumonia: a systematic review of the literature. Front Med 7:170–186

    Article  Google Scholar 

  33. Fang L, Karakiulakis G, Roth M (2020) Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 32:171–189

    Google Scholar 

  34. Gurwitz D (2020) Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 1:4–19

    Google Scholar 

  35. Nejat R, Sadr S (2021) Are losartan and imatinib effective against SARS-CoV2 pathogenesis? A pathophysiologic-based in silico study. In Silico Pharmacol 9:1

    PubMed  Article  PubMed Central  Google Scholar 

  36. Bengtson CD, Montgomery RN, Nazir U, Satterwhite L, Kim MD, Bahr NC et al (2021) An open label trial to assess safety of losartan for treating worsening respiratory illness in COVID-19. Front Med 8:630209

    Article  Google Scholar 

  37. Izurieta HS, Chillarige Y, Kelman JA, Forshee R, Qiang Y, Wernecke M et al (2018) Statin use and risks of influenza-related outcomes among older adults receiving standard-dose or high-dose influenza vaccines through medicare during 2010-2015. Clin Infect Dis 67:378–387

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. Rodrigues-Diez RR, Tejera-Muñoz A, Marquez-Exposito L, Rayego-Mateos S, Santos Sanchez L, Marchant V et al (2020) Statins: could an old friend help in the fight against COVID-19? Br J Pharmacol 177(21):4873–4886

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. Lin S, Chen Y, Lin Y, Hsieh Y, Wang S, Lin Y et al (2007) Pravastatin induces thrombomodulin expression in TNFα-treated human aortic endothelial cells by inhibiting Rac1 and Cdc42 translocation and activity. J Cell Biochem 101:642–653

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. Dong L, Hu S, Gao J (2020) Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther 14:58–60

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. Fu B, Xu X, Wei H (2020) Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med 18:164–178

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. DeGrado JR, Szumita PM, Schuler BR, Dube KM, Linox J, Kim EY et al (2020) Evaluation of the efficacy and safety of inhaled epoprostenol and inhaled nitric oxide for refractory hypoxemia in patients with coronavirus disease 2019. Crit Care Explor 2:e0259

    PubMed  PubMed Central  Article  Google Scholar 

  43. Khan FA, Stewart I, Fabbri L, Moss S, Robinson K, Smyth AR et al (2021) Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19. Thorax 12:21–26

    Google Scholar 

  44. Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I et al (2020) Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheum 2:E393–E400

    Article  Google Scholar 

  45. Kooistra EJ, Waalders NB, Grondman I, Janssen NA, de Nooijer A, Netea MG et al (2020) Anakinra treatment in critically ill COVID-19 patients: a prospective cohort study. Crit Care 24:688

    PubMed  PubMed Central  Article  Google Scholar 

  46. Filocamo G, Mangioni D, Tagliabue P, Aliberti S, Costantino G, Minoia F et al (2020) Use of anakinra in severe COVID-19: a case report. Int J Infect Dis 96:607–609

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z et al (2020) The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol 214:108393

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. D'Alessio A, Del Poggio P, Bracchi F, Cesana G, Sertori N, Di Mauro D et al (2021) Low-dose ruxolitinib plus steroid in severe SARS-CoV-2 pneumonia. Leuk 35:635–638

    CAS  Article  Google Scholar 

  49. Aryal MR, Gosain R, Donato A, Pathak R, Bhatt V, Katel A et al (2020) Venous thromboembolism in COVID-19: towards an ideal approach to thromboprophylaxis, screening, and treatment. Curr Cardiol Rep 22:52–69

    PubMed  PubMed Central  Article  Google Scholar 

  50. Flaczyk A, Rosovsky RP, Reed CT, Bankhead-Kendall B, Bittner E, Chang M (2020) Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations. Crit Care 24:559

    PubMed  PubMed Central  Article  Google Scholar 

  51. Montelongo-Jauregui D, Vila T, Sultan AS, Jabra-Rizk MA (2020) Convalescent serum therapy for COVID-19: a 19th century remedy for a 21st century disease. PLoS Pathog 16(8):e1008735

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J et al (2020) Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci 117(17):9490–9496

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. Hu X, Hu C, Jiang D, Zuo Q, Li Y, Wang Y et al (2020) Effectiveness of convalescent plasma therapy for COVID-19 patients in Hunan, China. Dose-Response 18(4):155

    Article  CAS  Google Scholar 

  54. Liu S, Lin H, Baine I, Wajnberg A, Gumprecht J, Rahman F et al (2020) Convalescent plasma treatment of severe COVID-19: a propensity score–matched control study. Nat Med 26:1708–1713

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  55. Zeng H, Wang D, Nie J, Liang H, Gu J, Zhao A et al (2020) The efficacy assessment of convalescent plasma therapy for COVID-19 patients: a multi-center case series. Sig Transduct Target Ther 5:219

    CAS  Article  Google Scholar 

  56. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J et al (2020) Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 323(16):1582–1589

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Barh D, Tiwari S, Andrade B, Giovanett M, Costa E, Kumavath R et al (2020) Potential chimeric peptides to block the SARS-CoV-2 spike receptor-binding domain [version 1; peer review: 1 approved]. F1000 Res 9:576–590

    CAS  Article  Google Scholar 

  58. Kruse RL (2020) Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000 Res 9:72–91

    CAS  Article  Google Scholar 

  59. Zhao J, Zhu M, Jiang H, Shen S, Su X, Shi Y (2019) Combination of sphingosine-1-phosphate receptor 1 (S1PR1) agonist and antiviral drug: a potential therapy against pathogenic influenza virus. Sci Rep 9:5272

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. Zhou Y, Cui C, Ma X, Luo W, Zheng S, Qiu W (2020) Nuclear factor κB (NF-κB)–mediated inflammation in multiple sclerosis. Frontiers Immun 11:391–405

    CAS  Article  Google Scholar 

  61. Hao S, Jin D, Zhang S, Qing R (2020) QTY code-designed water-soluble fc-fusion cytokine receptors bind to their respective ligands. QRB Discov 1:18–30

    Article  CAS  Google Scholar 

  62. Gao Y, Chen X, Fang Y (2020) 2019 novel coronavirus infection and gastrointestinal tract. J Dig Dis 21:125–126

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Messina F, Giombini E, Agrati C, Vairo F, Bartoli T, Al Moghazi S et al (2020) COVID-19: viral–host interactome analyzed by network based-approach model to study pathogenesis of SARS-CoV-2 infection. J Transl Med 18:233–250

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Cava C, Bertoli G, Castiglioni I (2020) A protein interaction map identifies existing drugs targeting SARS-CoV-2. BMC Pharmacol Toxicol 21:65

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

None.

Funding

None.

Author information

Authors and Affiliations

Authors

Contributions

EE conceptualized the project and prepared the manuscript. AA and FS gave technical inputs in revision of the manuscript. The authors have read and approved the manuscript.

Corresponding author

Correspondence to Engy Elekhnawy.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests..

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Elekhnawy, E., Kamar, A.A. & Sonbol, F. Present and future treatment strategies for coronavirus disease 2019. Futur J Pharm Sci 7, 84 (2021). https://doi.org/10.1186/s43094-021-00238-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43094-021-00238-y

Keywords

  • COVID-19
  • SARS-Cov-2
  • Cytokine storm
  • Respiratory distress syndrome