1. Suppressing Over-Activated Immune Responses
In patients with severe COVID-19, pro-inflammatory cells such as macrophages and neutrophils secrete high levels of inflammatory cytokines, leading to excess inflammation and potentially resulting in multi-organ failure and systemic collapse 
Several drug treatments have shown clinical benefits in COVID-19 patients by targeting the excessive immune response, including steroids, anti-cytokines, kinase inhibitors and selective serotonin reuptake inhibitors (SSRIs), as well as drugs that have undergone advanced clinical examination such as Sabizabulin, Vilobelimab, and Metformin.
Steroids have shown promise as potent anti-inflammatory agents in treating the “cytokine storm”, which, as has been mentioned above, is a hallmark of severe COVID-19. Dexamethasone, a steroid recommended for use in COVID-19 patients, has been shown to reduce mortality rates by approximately 33% in mechanically ventilated patients and about 20% in patients requiring noninvasive oxygen treatment. Recent studies have estimated that treatment with Dexamethasone saved the lives of about one million COVID-19 patients worldwide as of March 2021 
A phase 2 clinical trial of early treatment with the inhaled steroid Budesonide in mild–moderate COVID-19 patients demonstrated effectiveness in reducing rates of emergency room visits and hospitalizations, shortening recovery time, and improving clinical symptoms 
These findings underscore the potential of steroid treatment at all stages of COVID-19 and other respiratory diseases caused by pathogens.
Progressive elevation of various inflammatory cytokines, including Interleukin-6 (IL-6), IL-1β and granulocyte–macrophage colony-stimulating factor (GM-CSF), is directly associated with disease severity. Significantly higher serum levels of pro-inflammatory cytokines are observed in critically ill patients, prompting specific anti-cytokine treatment for prevention of tissue damage 
. There are several possible treatments that suppress excessive inflammatory response, including the use of antibodies that specifically target different cytokines (or their receptors) to neutralize them and prevent their pro-inflammatory activities.
Monoclonal Antibodies Targeting IL-6 Receptor
Monoclonal antibodies against cytokine IL-6 have shown promise in mitigating the pathology and “cytokine storm” associated with severe COVID-19 
Tocilizumab is a monoclonal antibody that targets the IL-6 receptor. This drug has demonstrated efficacy when administered to severely ill patients within two days of admission to an intensive care unit (a multicenter cohort study of 4485 patients conducted from March to May 2020). A significant reduction in mortality within 30 days was observed (27.5% in the treated group compared to 37.1% in the control group) 
. A subsequent study involving over 4000 patients demonstrated a reduction in hospital stay time (as measured by the number of patients discharged within 28 days, 57% in the treated group compared to 50% in the control group), as well as a reduction in the likelihood of invasive mechanical ventilation and mortality (35% mortality in the treated group compared to 42% in the control group) 
. In June 2021, the drug was granted emergency use authorization by the FDA for use in combination with steroids in hospitalized COVID-19 patients who require supplemental oxygen or mechanical ventilation (noninvasive, invasive and extracorporeal membrane oxygenation (ECMO)) (https://www.fda.gov/media/150319/download, accessed on 9 May 2023). This emergency use authorization was based, in addition to the aforementioned studies, on smaller clinical studies conducted on hundreds of patients (https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-treatment-covid-19, accessed on 9 May 2023). On 21 December 2022, the drug (in combination with systemic steroids) was granted formal FDA approval (https://www.gene.com/media/press-releases/14979/2022-12-21/fda-approves-genentechs-actemra-for-the-, accessed on 9 May 2023).
Sarilumab, another monoclonal antibody targeting the IL-6 receptor, has been found to be effective in reducing mortality rates in COVID-19 cases. In meta-analyses comparing Sarilumab to Tocilizumab, Sarilumab showed potential effectiveness, although Tocilizumab appeared to be more effective overall 
. However, it is worth noting that a phase 3 clinical trial of Sarilumab did not demonstrate significant improvement compared to those who were not treated with the drug. It is important to keep in mind that only 60% of the study participants were treated with steroids 
Anakinra, a recombinant Interleukin-1 (IL-1) receptor antagonist, is a drug that inhibits the activity of cytokine IL-1. Several studies have shown that IL-1 plays a key role in the development of the “cytokine storm” in patients infected with SARS-CoV-2, and that the levels of the pro-inflammatory cytokine IL-1β increase significantly following infection 
. In a phase 3 clinical trial involving 600 severe COVID-19 patients, treatment with Anakinra (administered in combination with the steroid Dexamethasone) resulted in a significant clinical benefit, including a significant decrease in mortality rates compared to the control group who received Dexamethasone alone. This effect was observed until day 28 from the start of treatment, along with a decrease in the length of hospitalization or stay in the intensive care unit. A systematic review and individual patient-level meta-analysis 
of hundreds of patients revealed that Anakinra significantly lowers the risk of mortality on the 28th day in hospitalized patients in a moderate–severe condition who are not treated with Dexamethasone, especially when the CRP (C reactive protein) levels in the blood are above 100 mg/mL.
Observational and retrospective studies, as well as smaller clinical trials, have also demonstrated the efficacy of Anakinra in improving survival rates, preventing deterioration to pulmonary failure, and improving inflammation indicators in COVID-19 patients 
On 2 November 2020, Anakinra received emergency use authorization (EUA) from the FDA for the treatment of severe COVID-19 patients who are hospitalized with pneumonia, are in need of oxygen support, and are also characterized by elevated levels of soluble urokinase plasminogen activator receptor (suPAR) in plasma. The clinical efficacy of the drug treatment was demonstrated in a subgroup analysis and was maintained up to 90 days after treatment onset 
Infliximab is a monoclonal antibody against TNFα. When administered alone in a phase 3 clinical trial, a 41% relative reduction in measured mortality rates up to day 28 of treatment was observed (from 14.5% in the control group to 10.1% in the treatment group, 517 patients in moderate or severe condition). Chances for clinical status improvement were also higher (43.8% increase) up to day 14 from treatment start. The drug was administered in combination with steroids or Remdesivir 
1.3. Kinase Inhibitors
Janus Kinase (JAK) Inhibitors
The JAK inhibitors Baricitinib and Tofacitinib are drugs used to treat joint inflammatory diseases by inhibiting the JAK1/2 and JAK1/JAK3 enzymes, respectively 
. Imatinib inhibits the Bcr-Abl kinase by binding to its active site for Chronic Myeloid Leukemia (CML) treatment.
A meta-analysis of four controlled clinical trials (10,815 patients) showed that treatment with Baricitinib in hospitalized COVID-19 patients led to a significant decrease in a 28-day mortality, as well as a positive trend (although not statistically significant) in the reduction in invasive mechanical ventilation (IMV) or ECMO support 
. The drug was approved for emergency use in hospitalized COVID-19 patients supported by noninvasive oxygen (or on mechanical ventilation) in October 2022 as a standalone treatment, following the previous approval of combination therapy with Remdesivir. The combination therapy of Baricitinib and Remdesivir led to a faster recovery compared to that of Remdesivir alone 
and was characterized by a better safety profile compared to that of the Dexamethasone–Remdesivir combination 
Similarly, treatment with Tofacitinib led to a significant decrease in mortality or in the development of respiratory failure (18.1% vs. 29% in the placebo group) within 28 days. Death from any cause through day 28 occurred in 2.8% vs. 5.5% of those in the Tofacitinib or placebo group, respectively (STOP-COVID trial 
Imatinib has revolutionized the treatment of Chronic Myeloid Leukemia (CML) by dramatically improving patient outcomes. It works by binding to the active site of the Bcr-Abl kinase and blocking its activity, which in turn inhibits the proliferation and survival of leukemic cells. In the past, it was demonstrated that the drug leads to hemodynamic improvements in patients diagnosed with pulmonary arterial hypertension through protective effects on healthy blood vessels 
by, among other things, inhibiting the influence of inflammatory cytokines such as IL-6 and TNFα 
. Experiments in animal models indicate that Imatinib protects the endothelial barrier in inflammatory conditions and prevents the development of inflammation by inhibiting the Abl kinase 
. Isolated clinical case reports have pointed to the potential for rapid correction of vascular leakage and improvement in clinical status 
, as well as a beneficial effect in COVID-19 patients 
. A controlled clinical trial was conducted on COVID-19 hospitalized patients who required noninvasive oxygen support, which showed that the drug did not benefit in terms of achieving endpoint of the trial (48 h cessation of respiratory support). However, the mortality rates were lower in the Imatinib-treated group (8%) compared to the control group (14%), and the median time supported by mechanical ventilation was significantly lower in the treatment group (7 vs. 12 days) 
. The improvement in survival was unadjusted, but a significant statistical effect was still observed even after adjustment. A follow-up study that examined the 90-day mortality rates from the start of treatment also showed a significant improvement in survival rates, with mortality rates of 9.1% and 16.5% in the treatment and control groups, respectively (which remained significant even after adjustment).
1.4. Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine/Fluvoxamine, used to treat depression, are medications that belong to the SSRIs family. These medications have an anti-inflammatory effect that is mediated through agonism to sigma-1 receptors (S1Rs), which leads to a decrease in cytokine production 
. In a large, multi-center retrospective study that included 83,584 COVID-19 patients hospitalized in 87 medical centers in the United States, an inverse correlation was observed between the administration of these medications and severity of illness and death. Specifically, clinical studies, some of which are ongoing (although relatively small), have shown that treatment with Fluvoxamine reduces the risk of clinical deterioration in non-hospitalized patients 
, including early-stage treatment in the at-risk population 
. It should be emphasized, though, that two large clinical trials failed to show a beneficial effect of Fluvoxamine treatment. However, one of these studies included only a vaccinated population 
, and in the other study, the median age was below 50 years, and only half of the participants were unvaccinated. In addition, the dosage chosen for treatment was lower than the dosages chosen for the trials described above 
. In addition, treatment with oral Fluvoxamine plus inhaled budesonide among highly vaccinated, high-risk outpatients with early COVID-19 reduced the risk of deteriorating to severe disease in comparison to placebo-treated patients 
. With respect to infections with the Omicron variant, according to a recently published study 
, antidepressant use as a whole (non-SSRIs, SSRIs and fluoxetine specifically) was associated with a lower risk of severe COVID-19 (ICU admission and inpatient death). This provides supportive evidence for the treatment potential of all antidepressants for severe COVID-19. Another study that has not yet undergone peer review 
suggests that SSRIs with agonist activity at the sigma-1 may significantly reduce long-term complications of COVID-19 (post-acute sequelae of COVID-19, “Long-COVID”). Several mechanisms have been proposed so far for the beneficial effects of these drugs, including inhibition of the enzyme acid sphingomyelinase (ASM) and anti-inflammatory effects. ASM 
is responsible for converting sphingomyelin into ceramide and phosphorylcholine. Ceramide is a central component of the cell membrane through which SARS-CoV-2 penetrates into the intracellular compartment. As for the anti-inflammatory activity, the drugs act on several levels: (i) through binding to S1Rs receptors, as mentioned, which leads to reduced activity of the endonuclease inositol-requiring enzyme 1 (IRE1) and decreased expression of cytokines without inhibiting classic inflammatory mechanisms; (ii) inhibition of classic inflammatory elements, such as nuclear factor κB, inflammasome, TLR4, and PPARγ; and (iii) inhibition of ASM on endothelial and immune system cells 
. Additional mechanisms have been proposed to explain the beneficial effect of these drugs, such as anticoagulant/antiplatelet elements, direct antiviral elements and more 
Sabizabulin is a chemotherapeutic drug currently undergoing clinical trials for the treatment of prostate cancer. It works through microtubule disruption, which is a key component of the cytoskeleton. Sabizabulin is bound to the active site of Colchicine (another drug that has shown potential as a treatment for COVID-19, but eventually failed to prove clinical efficacy 
Compared to Colchicine, Sabizabulin binds with high affinity to the “Colchicine binding” pocket in the β-tubulin subunit, and has a superior pharmacokinetic profile, resulting in longer circulatory presence 
. The development of Sabizabulin included in vitro experiments that demonstrated potential anti-inflammatory effects, although these data have not yet been published in the scientific literature (https://www.biospace.com/article/veru-s-lead-compound-shows-promise-as-antiviral-anti-inflammatory-therapeutic-for-covid-19, accessed on 18 May 2023). In a phase 3 clinical trial involving 204 participants (134 of whom were treated with Sabizabulin), a significant decrease in mortality rates (24.9% absolute reduction), a 43% relative reduction in ICU days (p
= 0.0013), a 49% relative reduction in days on mechanical ventilation (p
= 0.0013), and a 26% relative reduction in days in the hospital (p
= 0.0277) were demonstrated in moderately to severely ill patients (with a high risk of ARDS and death) compared to the placebo group 
. Despite these results, the FDA denied emergency use authorization (EUA) for the treatment of COVID-19 with Sabizabulin in early March 2023.
On the one hand, the complement system plays an important role in pathogen clearance. On the other, unregulated complement activation plays a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic viruses including influenza A viruses H5N1, H7N9 and severe acute respiratory syndrome coronavirus (SARS-CoV-1). In particular, the C5a component of the complement system and its receptor, C5aR1, play an important role in inflammatory processes, particularly in tissue and blood vessel damage by recruiting neutrophils and monocytes to the site of inflammation. Blockade of C5a signaling has been implicated in the treatment of ALI induced by highly pathogenic viruses 
Vilobelimab is a monoclonal antibody (mAb) that targets C5a. During the COVID-19 pandemic, it has been shown that levels of C5a in COVID-19 patients are positively correlated with disease severity, and that C5aR1 antagonists prevent the development of acute lung injury in mice exposed to SARS-CoV-2 
. Results from a phase 3 clinical trial conducted in approximately 370 mechanically ventilated COVID-19 patients demonstrated that treatment with Vilobelimab in addition to standard care leads to a significant improvement in survival rates (a 31% mortality compared to 40% in the control group) 
. On April 2023, it was declared that circumstances exist justifying the authorization of emergency use of Vilobelimab (https://www.fda.gov/media/166823/download
, accessed on 18 May 2023).
Metformin is a drug used to treat type II diabetes mellitus (T2DM) with anti-inflammatory activity, including suppression of cytokine release (IL-6 and IL-1β), inhibition of inflammasome activity (including in mice, 
), activation of autophagy, and more. The drug improved survival rates in mice in an acute lung injury model 
. Observational retrospective studies and meta-analyses have shown a trend of decreased mortality, severity of illness, and hospitalizations following the use of this drug, mainly in patients with T2DM 
. A retrospective analysis of approximately 6000 COVID-19 patients demonstrated a significant decrease in mortality in women (but not in men) with T2DM or obesity who were treated with Metformin 
. Since T2DM is a major risk factor affecting prognosis in COVID-19 patients, alongside other risk factors that are associated with this vulnerable population (such as age and obesity) 
, it is important to examine in depth whether the anti-inflammatory effects or the anti-diabetic properties of the drug are the leading factors contributing to its beneficial effects. A controlled clinical trial (including approximately 1450 COVID-19 patients without diabetic background) showed no clear effect of Metformin on endpoints. However, a potential effect in preventing more severe components (such as intensive care unit admission, hospitalization, and mortality) was demonstrated. It should be noted that the study population was selected based on weight (all had obesity) and had a relatively young median age (46). In addition, half of the study participants were vaccinated 
. Therefore, it is possible that these data partly reflect a more pronounced effect of the drug. In another controlled study that examined early treatment with Metformin in non-hospitalized patients, the drug’s efficacy was not demonstrated in terms of hospitalization rates within 28 days of treatment initiation, as well as viral clearance and mortality 
. However, Metformin administration to the same sub-population (early outpatient treatment) resulted in a 41% relative decrease and a 4.1% absolute decrease in the Long-COVID (≥9 months after infection) incidence (results taken from a phase 3 trial 
). This metformin effect was consistent across subgroups, including viral variants.
Abatacept is an analogue of CTLA-4 that prevents the generation of a co-stimulatory signal in antigen-presenting cells, thereby preventing overactivation of the immune system. Treatment with the drug as a single dose led to a decrease in mortality rates documented up to day 28 after treatment: 11% in the treatment group (509 patients with moderate or severe conditions) as opposed to 15.1% in the control group (a decrease of 38%, odds ratio of 0.62) 
. At the pandemic onset, it was hypothesized that treatment with Abatacept, which blocks the pro-inflammatory axis of the CD80/86 co-stimulatory signal, could be an effective approach in COVID-19 patients; this due to the suppression of the “cytokine storm”, particularly IL-6 levels (which are highly correlated with severe disease). Additionally, the drug is expected to suppress the complement system and the overactivation of the immune response mediated by B lymphocytes 
2. Immune Response Stimulation
The interferon response is the first line of defense against viruses. Detection of viruses by the innate immune system leads to the production of type I (IFNα, IFNβ) and III (IFNλ) interferon responses 
. Accordingly, one mechanism viruses use to evade or suppress the immune response is by inhibiting the interferon response, as observed for SARS-CoV-2 
. An external activation of the immune response by the administration of exogenous interferons is a well-known approach for combating viruses such as Hepatitis B, Hepatitis C, and HIV-1 
. It should be noted that interferon therapy is not without side effects due to the inflammatory response and cytokine release downstream of interferon signaling, as observed for type I interferons 
, which requires careful dosage adjustment. In contrast, type III interferon response does not promote inflammation 
, and therefore may have a more favorable safety profile. On top of this, a study that examined the immune response in COVID-19 patients treated with IFNλ found that the treatment lead to a boosted innate response without negatively affecting the adaptive immune response 
. Additionally, in a mouse model, full protection was achieved against lethal exposure to hCoV and MERS-CoV following treatment with IFNλ (prophylactic or post-infection) 
The suppression of the interferon response in COVID-19 patients, alongside the potential therapeutic value of IFNs, has led to pre-clinical and clinical studies to evaluate the effectiveness of this treatment. Some of the clinical trial results are indeed very encouraging, particularly in terms of therapeutic intervention in the early stages of the disease, and in particular regarding IFNλ.
The administration of Pegylated IFNλ-1a has previously been examined for the treatment of Hepatitis B/C/D. A single subcutaneous injection within 7 days of symptom onset led to a 50% reduction (2.7% compared to 5.6% in the control group) in hospitalizations and emergency room (ER) admissions by day 28 of treatment, as well as a 60% decrease in mortality. This was demonstrated in a phase 3 clinical trial in non-hospitalized patients (approximately 900 patients received Pegylated IFNλ-1a out of the 1900 patients enrolled), the majority of whom (84%) were vaccinated against COVID-19. The treatment was effective for infection with various SARS-CoV-2 variants, including Omicron 
SNG001, IFN β-1a, which is administered by nebulization to hospitalized patients for 14 days, demonstrated therapeutic potential (rapid recovery and higher likelihood of clinical improvement) alongside a positive safety profile in a phase 2 clinical trial of about 100 participants (half of whom received SNG001) 
. Although the final and decisive stage of the trial did not lead to similar conclusions, it cannot be ruled out that this treatment might be more effective if administered at different time points (e.g., early treatment or prophylactic treatment) or in combination with other drugs.
Nitazoxanide, an anti-parasitic drug from the thiazolide family, activates the innate immune system by upregulating the expression of type I IFN pathway genes TLR7 and TLR8. These are involved in antiviral activity against various viruses 
. Additionally, the drug has anti-bacterial activity 
. A randomized clinical trial in approximately 400 mild COVID-19 patients who received Nitazoxanide for up to three days from symptom onset for a total of five days showed that the drug led to faster virus clearance (29.9% negative swabs in the study group versus 18.2% in the control group on day 5 of treatment) and a significant reduction in viral load 
. In another experiment (with only 50 hospitalized mild COVID-19 patients), the treatment led to a significant decrease in hospitalization time (6.6 days in the study group versus 14 days in the control group), a decrease in inflammatory markers (including TNFα and IL-6), and an increase in negative PCR tests on day 21 after treatment initiation 
. However, treatment with Nitazoxanide in hospitalized COVID-19 patients who required oxygen support did not lead to a decrease in mortality or clinical deterioration rates (defined as transfer to an intensive care unit). Nevertheless, a benefit was observed in terms of a shorter hospitalization time, clinical improvement, decreased need for oxygen, and decreased inflammatory markers on day 7 after treatment initiation 
. In addition to activating the innate immune system and the anti-inflammatory effects of the drug (also demonstrated in preclinical models 
), Nitazoxanide mediates cellular antiviral effects via phosphorylation of eukaryotic translation initiation factor 2-α (eIF2α) 
3. Disruption to Cellular Mechanisms Involved in the Viral Life Cycle and Survival
Plitidepsin is a chemotherapeutic drug used to treat plasma cell disorders (multiple myeloma). Plitidepsin inhibits the eukaryotic translation-elongation-factor-1A (eEF1A), an endogenous protein involved in the translation process of viral and cellular proteins. The drug was shown to inhibit viral replication, including in mice infected with SARS-CoV-2. It should be noted that the antiviral activity of the drug against SARS-CoV-2 is 27.5 times more potent than that of Remdesivir 
, and relevant clinical findings suggest potential effectiveness 
. The drug is currently undergoing clinical evaluation (phase 3) in combination with Dexamethasone in approximately 610 patients (ClinicalTrials.gov
, NCT04784559). In terms of the drug’s potential as a broad-spectrum antiviral treatment, it has been shown in the past that eEF1A plays an important role in the replication of RNA viruses 
, including influenza A 
and respiratory syncytial virus (RSV) 
. Additional research indicates that the interaction of eEF1A with a specific RNA segment (3′ (+) stem-loop RNA) of West Nile virus accelerates virus synthesis 
. This interaction is relevant for all Flaviviridae virus family members.
3.2. HDTs with Antiviral Activity
For some of the drugs mentioned above (demonstrated as having potential efficacy against COVID-19 by reducing excessive inflammatory response), an additional mechanism of direct antiviral activity is involved by interfering with cellular mechanisms involved in the viral life cycle and survival.
In addition to its anti-inflammatory activity discussed earlier, Baricitinib acts directly by potentially inhibiting numb-associated kinases (AAK1, GAK, BIKE, and STK16) that influence AP-2, a scaffolding protein vital for the entry and proliferation of the virus into cells 
. It has been previously shown that inhibiting this kinase family leads to decreased infectivity of various viruses, including Dengue, SARS-CoV-1, and Ebola 
Direct antiviral activity is attributed to microtubule (MT) inhibition as MTs play an important role in intracellular transport of virus particles and regulation of other processes 
. The importance of microtubules in viral attachment and intracellular transport has been demonstrated for RNA and DNA viruses. Microtubule inhibitors have also shown direct antiviral activity against SARS-CoV-2 
In addition to the immunomodulatory activity mentioned above, Imatinib has shown antiviral activity (inhibition of virus replication) against MERS and SARS-CoV-1 in the early stages of infection, after internalization and endosomal trafficking, by inhibiting viral fusion to the endosome membrane 
. Specific studies on SARS-CoV-2 have shown direct activity on the ACE2 receptor (enzymatic activation and allosteric inhibition of ACE2 binding to spike protein), as well as inhibition of viral entry into cells (endocytosis- and membrane-fusion routes) 
In addition to its suppressing the over-activated immune response (discussed earlier), a direct antiviral effect was demonstrated for Metformin via 5′-AMP-activated protein kinase (AMPK) activation 
. An antiviral effect of the drug was demonstrated against various viruses, i.e., Zika, Dengue 
and Hepatitis C