Clinically Evaluated COVID-19 Drugs with Therapeutic Potential for Biological Warfare Agents
Abstract
:1. Introduction
2. Host-Directed Therapies (HDTs) for the Treatment of COVID-19
2.1. Suppressing Over-Activated Immune Responses
2.1.1. Steroids
Dexamethasone
Budesonide
2.1.2. Anti-Cytokines
Monoclonal Antibodies Targeting IL-6 Receptor
- 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) [15]. 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) [16]. 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 [17,18]. 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 [19].
Anakinra
Infliximab
Monoclonal Antibodies against Granulocyte–Macrophage Colony-Stimulating Factor
- Lenzilumab is a monoclonal antibody that targets GM-CSF. Results from a phase 3 clinical trial in approximately 500 critically ill patients (without “cytokine storm” or invasive mechanical ventilation, also treated with Remdesivir and/or steroids) show that treatment with the drug led to a statistically significant (p < 0.04), though mild (84% versus 78%) increase in survival rates in non-invasively mechanically ventilated patients up to day 28 of treatment compared to patients who did not receive Lenzilumab. However, according to a statement by Humanigen, the company which develops this drug, a separate clinical trial examining the effect of the drug in combination with Remdesivir (compared to Remdesivir alone) showed no benefit compared to treatment with Remdesivir alone (https://s28.q4cdn.com/539885110/files/doc_news/Humanigen-Receives-Preliminary-Topline-Data-From-NIHNIAID-Study-of-Lenzilumab-in-ACTIV-5BET-B-2022.pdf, accessed on 18 May 2023).
- Otilimab is another monoclonal antibody that targets and inhibits the activity of the cytokine GM-CSF. In a phase 2 clinical trial (OSCAR trial) in COVID-19 patients with systemic inflammation, Otilimab did not demonstrate efficacy in patients aged 18 and older, but there was a partial positive trend observed in the subgroup of patients aged 70 and older in terms of survival rates and decrease in inflammatory markers (this trend was not confirmed in a separate successive study; however, in this separate study, a reduction in inflammatory markers was observed with Otilimab, in addition to the establishment of an acceptable safety profile) [30]. While these results suggest some potential benefit of treatments that target the anti-GM-CSF mechanism in COVID-19 patients, further research is needed to confirm these findings.
2.1.3. Kinase Inhibitors
Janus Kinase (JAK) Inhibitors
- 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 [32,33]. 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 [34] and was characterized by a better safety profile compared to that of the Dexamethasone–Remdesivir combination [35].
- 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 [36]).
Imatinib
2.1.4. Selective Serotonin Reuptake Inhibitors (SSRIs)
2.1.5. Sabizabulin
2.1.6. Vilobelimab
2.1.7. Metformin
2.1.8. Abatacept
2.2. Immune Response Stimulation
2.2.1. Interferons
Pegylated IFNλ-1a
IFN β-1a
2.2.2. Nitazoxanide
2.3. Disruption to Cellular Mechanisms Involved in the Viral Life Cycle and Survival
2.3.1. Plitidepsin
2.3.2. HDTs with Antiviral Activity
Baricitinib
Sabizabulin
Imatinib
Metformin
3. Antiviral Treatments against SARS-CoV-2
3.1. Protease Inhibitors
3.2. Remdesivir
3.3. Molnupiravir
3.4. Inhaled Nitric Oxide
4. Effective COVID-19 Treatments and Their Potential Efficacy towards Biological Threat Agents
- Combining antibodies directed against Y. pestis with methylprednisolone in mice exposed subcutaneously to Y. pestis improved survival and inflammatory markers tested [141]. In a pneumonic plague model, pre-exposure treatment with the inhaled steroid Fluticasone followed by late antibiotic treatment also led to decreased inflammatory markers and increased survival rates [142]. In addition, treatment with steroids [143] or Anakinra [144] in pre-clinical models of respiratory exposure to ricin led to increased survival rates and improved pathology (in the case of toxins, where the damage is sterile, there is no concern regarding immune modulation and infectivity). Combination therapy of Etanercept, a monoclonal antibody against TNFα, with the antiviral drug Cidofovir, led to clinical improvement and increased survival in mice following respiratory infection with the Ectromelia virus (mousepox, an animal model of smallpox) [145].
- Some of the drugs discussed in this review have direct or indirect antimicrobial activities, such as Metformin, which has been shown to have antiviral [120,146] and antibacterial [147] activity when used in combination with other drugs. Metformin’s effectiveness against flavivirus (Zika and Dengue viruses) replication has been demonstrated in cells [148]. SSRIs, such as Fluoxetine, also have direct antibacterial activity and synergistic activity with various antibiotics [149]. Furthermore, Fluoxetine significantly inhibited cell infection with the Ebola virus through inhibition of the enzyme acid sphingomyelinase [150].
- Concerning biological threat viral agents, kinase inhibitors, including Imatinib, Baricitinib, and Tofacitinib, are at different stages of clinical and preclinical research to evaluate their effectiveness as broad-spectrum antiviral treatments [153].
5. Summary
- A broad coverage range: viruses, bacteria, toxins and more due to the endogenous nature of the effect.
- Reduced risk of developing microbial resistance (namely the increased potential of coverage of variants, antibiotic resistant bacteria and more).
- Mesenchymal stromal cells (MSCs), which have demonstrated potential efficacy in both preclinical models and clinical settings against infectious diseases (bacterial, viral, etc.) via direct antimicrobial mechanisms or host-directed therapy (HDT). However, MSCs also face several challenges such as safety and regulatory issues [155]. Clinical trials with MSCs in COVID-19 patients, as they become available [156], may help address these gaps in safety, efficacy, and regulation, potentially rendering this platform more applicable in the foreseeable future. MSCs mode of action may very well be relevant to many other microbial infections.
- Drug delivery systems and novel formulations are expected to streamline and optimize therapeutic treatments. Among other objectives, these systems aim to enable more convenient treatments (e.g., inhaled, per os or ambulatory-based administration versus the current parenteral administration in hospitals), reduce drug side effects (through local and organ-targeted delivery) and/or improve bioavailability. For example, a phase 1 clinical trial has been conducted to test an inhalable or intranasal formulation of the drug Niclosamide. Niclosamide is a drug possessing 40 times the potency of Remdesivir in Vero cells against SARS-CoV-2. However, it is not adequately absorbed when administered to COVID-19 patients [157].
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Msemburi, W.; Karlinsky, A.; Knutson, V.; Aleshin-Guendel, S.; Chatterji, S.; Wakefield, J. The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature 2023, 613, 130–137. [Google Scholar] [CrossRef]
- Hu, B.; Huang, S.; Yin, L. The Cytokine Storm and COVID-19. J. Med. Virol. 2021, 93, 250–256. [Google Scholar] [CrossRef]
- Qu, P.; Evans, J.P.; Faraone, J.N.; Zheng, Y.M.; Carlin, C.; Anghelina, M.; Stevens, P.; Fernandez, S.; Jones, D.; Lozanski, G.; et al. Enhanced Neutralization Resistance of SARS-CoV-2 Omicron Subvariants Bq.1, Bq.1.1, Ba.4.6, Bf.7, and Ba.2.75.2. Cell Host Microbe 2023, 31, 9–17.e3. [Google Scholar] [CrossRef]
- Bhalla, D.K.; Warheit, D.B. Biological agents with potential for misuse: A historical perspective and defensive measures. Toxicol. Appl. Pharmacol. 2004, 199, 71–84. [Google Scholar] [CrossRef]
- Bugert, J.J.; Hucke, F.; Zanetta, P.; Bassetto, M.; Brancale, A. Antivirals in medical biodefense. Virus Genes 2020, 56, 150–167. [Google Scholar] [CrossRef] [Green Version]
- Wallis, R.S.; O’Garra, A.; Sher, A.; Wack, A. Host-Directed Immunotherapy of Viral and Bacterial Infections: Past, Present and Future. Nat. Rev. Immunol. 2023, 23, 121–133. [Google Scholar] [CrossRef]
- Gu, W.; Gan, H.; Ma, Y.; Xu, L.; Cheng, Z.J.; Li, B.; Zhang, X.; Jiang, W.; Sun, J.; Sun, B.; et al. The Molecular Mechanism of SARS-CoV-2 Evading Host Antiviral Innate Immunity. Virol. J. 2022, 19, 49. [Google Scholar] [CrossRef]
- Águas, R.; Mahdi, A.; Shretta, R.; Horby, P.; Landray, M.; White, L. Potential Health and Economic Impacts of Dexamethasone Treatment for Patients with COVID-19. Nat. Commun. 2021, 12, 915. [Google Scholar] [CrossRef]
- Ramakrishnan, S.; Nicolau, D.V.; Langford, B.; Mahdi, M.; Jeffers, H.; Mwasuku, C.; Krassowska, K.; Fox, R.; Binnian, I.; Glover, V.; et al. Inhaled Budesonide in the Treatment of Early COVID-19 (Stoic): A Phase 2, Open-Label, Randomised Controlled Trial. Lancet Respir. Med. 2021, 9, 763–772. [Google Scholar] [CrossRef]
- Han, H.; Ma, Q.; Li, C.; Liu, R.; Zhao, L.; Wang, W.; Zhang, P.; Liu, X.; Gao, G.; Liu, F.; et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. Microbes Infect. 2020, 9, 1123–1130. [Google Scholar] [CrossRef]
- Huang, Q.; Wu, X.; Zheng, X.; Luo, S.; Xu, S.; Weng, J. Targeting inflammation and cytokine storm in COVID-19. Pharmacol. Res. 2020, 159, 105051. [Google Scholar] [CrossRef]
- Mojtabavi, H.; Saghazadeh, A.; Rezaei, N. Interleukin-6 and severe COVID-19: A systematic review and meta-analysis. Eur. Cytokine Netw. 2020, 31, 44–49. [Google Scholar] [CrossRef]
- Thwaites, R.S.; Uruchurtu, A.S.S.; Siggins, M.K.; Liew, F.; Russell, C.D.; Moore, S.C.; Carter, E.; Abrams, S.; Short, C.-E.; Thaventhiran, T.; et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci. Immunol. 2021, 6, eabg9873. [Google Scholar] [CrossRef]
- Gupta, A.; Madhavan, M.V.; Sehgal, K.; Nair, N.; Mahajan, S.; Sehrawat, T.S.; Bikdeli, B.; Ahluwalia, N.; Ausiello, J.C.; Wan, E.Y.; et al. Extrapulmonary manifestations of COVID-19. Nat. Med. 2020, 26, 1017–1032. [Google Scholar] [CrossRef]
- Gupta, S.; Wang, W.; Hayek, S.S.; Chan, L.; Mathews, K.S.; Melamed, M.L.; Brenner, S.K.; Leonberg-Yoo, A.; Schenck, E.J.; Radbel, J.; et al. Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern. Med. 2021, 181, 41–51. [Google Scholar] [CrossRef]
- Recovery Collaborative Group. Tocilizumab in Patients Admitted to Hospital with COVID-19 (Recovery): A Randomised, Controlled, Open-Label, Platform Trial. Lancet 2021, 397, 1637–1645. [Google Scholar] [CrossRef]
- Domingo, P.; Mur, I.; Mateo, G.M.; del Mar Gutierrez, M.; Pomar, V.; de Benito, N.; Corbacho, N.; Herrera, S.; Millan, L.; Muñoz, J.; et al. Association between Administration of Il-6 Antagonists and Mortality among Patients Hospitalized for COVID-19: A Meta-Analysis. JAMA 2021, 326, 499–518. [Google Scholar]
- The REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with COVID-19. N. Engl. J. Med. 2021, 384, 1491–1502. [Google Scholar] [CrossRef]
- Lescure, F.X.; Honda, H.; Fowler, R.A.; Lazar, J.S.; Shi, G.; Wung, P.; Patel, N.; Hagino, O.; Bazzalo, I.J.; Casas, M.M.; et al. Sarilumab in Patients Admitted to Hospital with Severe or Critical COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet Respir. Med. 2021, 9, 522–532. [Google Scholar] [CrossRef]
- Mardi, A.; Meidaninikjeh, S.; Nikfarjam, S.; Zolbanin, N.M.; Jafari, R. Interleukin-1 in COVID-19 Infection: Immunopathogenesis and Possible Therapeutic Perspective. Viral Immunol. 2021, 34, 679–688. [Google Scholar] [CrossRef]
- Kyriazopoulou, E.; Huet, T.; Cavalli, G.; Gori, A.; Kyprianou, M.; Pickkers, P.; Eugen-Olsen, J.; Clerici, M.; Veas, F.; Chatellier, G.; et al. Effect of anakinra on mortality in patients with COVID-19: A systematic review and patient-level meta-analysis. Lancet Rheumatol. 2021, 3, e690–e697. [Google Scholar] [CrossRef]
- Cauchois, R.; Koubi, M.; Delarbre, D.; Manet, C.; Carvelli, J.; Blasco, V.B.; Jean, R.; Fouche, L.; Bornet, C.; Pauly, V.; et al. Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19. Proc. Natl. Acad. Sci. USA 2020, 117, 18951–18953. [Google Scholar] [CrossRef]
- Cavalli, G.; De Luca, G.; Campochiaro, C.; Della-Torre, E.; Ripa, M.; Canetti, D.; Oltolini, C.; Castiglioni, B.; Din, C.T.; Boffini, N.; et al. Interleukin-1 Blockade with High-Dose Anakinra in Patients with COVID-19, Acute Respiratory Distress Syndrome, and Hyperinflammation: A Retrospective Cohort Study. Lancet Rheumatol. 2020, 2, e325–e331. [Google Scholar] [CrossRef]
- Huet, T.; Beaussier, H.; Voisin, O.; Jouveshomme, S.; Dauriat, G.; Lazareth, I.; Sacco, E.; Naccache, J.-M.; Bézie, Y.; Laplanche, S.; et al. Anakinra for severe forms of COVID-19: A cohort study. Lancet Rheumatol. 2020, 2, e393–e400. [Google Scholar] [CrossRef]
- Kyriakoulis, K.G.; Kollias, A.; Poulakou, G.; Kyriakoulis, I.G.; Trontzas, I.P.; Charpidou, A.; Syrigos, K. The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis. J. Clin. Med. 2021, 10, 4462. [Google Scholar] [CrossRef]
- Kyriazopoulou, E.; Panagopoulos, P.; Metallidis, S.; Dalekos, G.N.; Poulakou, G.; Gatselis, N.; Karakike, E.; Saridaki, M.; Loli, G.; Stefos, A.; et al. An open label trial of anakinra to prevent respiratory failure in COVID-19. eLife 2021, 10, e66125. [Google Scholar] [CrossRef]
- Akinosoglou, K.; Kotsaki, A.; Gounaridi, I.-M.; Christaki, E.; Metallidis, S.; Adamis, G.; Fragkou, A.; Fantoni, M.; Rapti, A.; Kalomenidis, I.; et al. Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial. Eclinicalmedicine 2022, 56, 101785. [Google Scholar] [CrossRef]
- O’Halloran, J.A.; Kedar, E.; Anstrom, K.J.; McCarthy, M.W.; Ko, E.R.; Nunez, P.S.; Boucher, C.; Smith, P.B.; Panettieri, R.A., Jr.; de Tai, S.M.T.; et al. Infliximab for Treatment of Adults Hospitalized with Moderate or Severe COVID-19. medRxiv 2022. [Google Scholar] [CrossRef]
- Hamilton, J.A. GM-CSF in inflammation. J. Exp. Med. 2020, 217, e20190945. [Google Scholar] [CrossRef] [Green Version]
- Patel, J.; Bass, D.; Beishuizen, A.; Ruiz, X.B.; Boughanmi, H.; Cahn, A.; Colombo, H.; Criner, G.J.; Davy, K.; De-Miguel-Díez, J.; et al. A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR). Eur. Respir. J. 2023, 61, 2101870. [Google Scholar] [CrossRef]
- Traves, P.G.; Murray, B.; Campigotto, F.; Galien, R.; Meng, A.; Di Paolo, J.A. JAK Selectivity and the Implications for Clinical Inhibition of Pharmacodynamic Cytokine Signalling by Filgotinib, Upadacitinib, Tofacitinib and Baricitinib. Ann. Rheum. Dis. 2021, 80, 865–875. [Google Scholar] [CrossRef]
- Recovery Collaborative Group. Baricitinib in Patients Admitted to Hospital with COVID-19 (Recovery): A Randomised, Controlled, Open-Label, Platform Trial and Updated Meta-Analysis. Lancet 2022, 400, 359–368. [Google Scholar] [CrossRef]
- Selvaraj, V.; Finn, A.; Lal, A.; Khan, M.S.; Dapaah-Afriyie, K.; Carino, G.P. Baricitinib in hospitalised patients with COVID-19: A meta-analysis of randomised controlled trials. Eclinicalmedicine 2022, 49, 101489. [Google Scholar] [CrossRef]
- Kalil, A.C.; Patterson, T.F.; Mehta, A.K.; Tomashek, K.M.; Wolfe, C.R.; Ghazaryan, V.; Marconi, V.C.; Ruiz-Palacios, G.M.; Hsieh, L.; Kline, S.; et al. Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19. N. Engl. J. Med. 2021, 384, 795–807. [Google Scholar] [CrossRef]
- Wolfe, C.R.; Tomashek, K.M.; Patterson, T.F.; Gomez, C.A.; Marconi, V.C.; Jain, M.K.; Yang, O.O.; Paules, C.I.; Palacios, G.M.R.; Grossberg, R.; et al. Baricitinib versus Dexamethasone for Adults Hospitalised with COVID-19 (Actt-4): A Randomised, Double-Blind, Double Placebo-Controlled Trial. Lancet Respir. Med. 2022, 10, 888–899. [Google Scholar] [CrossRef]
- Guimarães, P.O.; Quirk, D.; Furtado, R.H.; Maia, L.N.; Saraiva, J.F.; Antunes, M.O.; Filho, R.K.; Junior, V.M.; Soeiro, A.M.; Tognon, A.P.; et al. Tofacitinib in Patients Hospitalized with COVID-19 Pneumonia. N. Engl. J. Med. 2021, 385, 406–415. [Google Scholar] [CrossRef]
- Overbeek, M.J.; Amerongen, G.P.V.N.; Boonstra, A.; Smit, E.F.; Vonk-Noordegraaf, A. Possible role of imatinib in clinical pulmonary veno-occlusive disease. Eur. Respir. J. 2008, 32, 232–235. [Google Scholar] [CrossRef] [Green Version]
- Stephens, R.S.; Johnston, L.; Servinsky, L.; Kim, B.S.; Damarla, M. The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice. Physiol. Rep. 2015, 3, e12589. [Google Scholar] [CrossRef]
- Aman, J.; Van Bezu, J.; Damanafshan, A.; Huveneers, S.; Eringa, E.C.; Vogel, S.M.; Groeneveld, A.J.; Noordegraaf, A.V.; Van Hinsbergh, V.W.; Amerongen, G.P.V.N. Effective Treatment of Edema and Endothelial Barrier Dysfunction With Imatinib. Circulation 2012, 126, 2728–2738. [Google Scholar] [CrossRef] [Green Version]
- Chislock, E.M.; Pendergast, A.M. Abl Family Kinases Regulate Endothelial Barrier Function In Vitro and in Mice. PLoS ONE 2013, 8, e85231. [Google Scholar] [CrossRef] [Green Version]
- Aman, J.; Peters, M.J.L.; Weenink, C.; Amerongen, G.P.V.N.; Noordegraaf, A.V. Reversal of Vascular Leak with Imatinib. Am. J. Respir. Crit. Care Med. 2013, 188, 1171–1173. [Google Scholar] [CrossRef]
- Morales-Ortega, A.; Bernal-Bello, D.; Llarena-Barroso, C.; Frutos-Pérez, B.; Duarte-Millán, M.; de Viedma-García, V.G.; Farfán-Sedano, A.I.; Canalejo-Castrillero, E.; Ruiz-Giardín, J.M.; Ruiz-Ruiz, J.; et al. Imatinib for COVID-19: A case report. Clin. Immunol. 2020, 218, 108518. [Google Scholar] [CrossRef]
- Aman, J.; Duijvelaar, E.; Botros, L.; Kianzad, A.; Schippers, J.R.; Smeele, P.J.; Azhang, S.; Bartelink, I.H.; Bayoumy, A.A.; Bet, P.M.; et al. Bogaard. Imatinib in Patients with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Clinical Trial. Lancet Respir. Med. 2021, 9, 957–968. [Google Scholar] [CrossRef]
- Duijvelaar, E.; Schippers, J.R.; Smeele, P.J.; de Raaf, M.A.; Vanhove, A.L.E.M.; Blok, S.G.; Twisk, J.W.R.; Noordegraaf, A.V.; de Man, F.S.; Bogaard, H.J.; et al. Long-term clinical outcomes of COVID-19 patients treated with imatinib. Lancet Respir. Med. 2022, 10, e34–e35. [Google Scholar] [CrossRef]
- de Brabander, J.; Duijvelaar, E.; Schippers, J.R.; Smeele, P.J.; Peters-Sengers, H.; Duitman, J.W.; Aman, J.; Bogaard, H.J.; van der Poll, T.; Bos, L.D. Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients. Eur. Respir. J. 2022, 60, 2200780. [Google Scholar] [CrossRef]
- Facente, S.N.; Reiersen, A.M.; Lenze, E.J.; Boulware, D.R.; Klausner, J.D. Fluvoxamine for the Early Treatment of SARS-CoV-2 Infection: A Review of Current Evidence. Drugs 2021, 81, 2081–2089. [Google Scholar] [CrossRef]
- Hoertel, N. Do the Selective Serotonin Reuptake Inhibitor Antidepressants Fluoxetine and Fluvoxamine Reduce Mortality among Patients with COVID-19? JAMA Netw. Open 2021, 4, e2136510. [Google Scholar] [CrossRef]
- Oskotsky, T.; Marić, I.; Tang, A.; Oskotsky, B.; Wong, R.J.; Aghaeepour, N.; Sirota, M.; Stevenson, D.K. Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA Netw. Open 2021, 4, e2133090. [Google Scholar] [CrossRef]
- Lenze, E.J.; Mattar, C.; Zorumski, C.F.; Stevens, A.; Schweiger, J.; Nicol, G.E.; Miller, J.P.; Yang, L.; Yingling, M.; Avidan, M.S.; et al. Fluvoxamine Vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial. JAMA 2020, 324, 2292–2300. [Google Scholar] [CrossRef]
- Reis, G.; Moreira-Silva, E.A.D.S.; Silva, D.C.M.; Thabane, L.; Milagres, A.C.; Ferreira, T.S.; dos Santos, C.V.Q.; Campos, V.H.d.S.; Nogueira, A.M.R.; de Almeida, A.P.F.G.; et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: The TOGETHER randomised, platform clinical trial. Lancet Glob. Health 2022, 10, e42–e51. [Google Scholar] [CrossRef]
- McCarthy, M.W.; Naggie, S.; Boulware, D.R.; Lindsell, C.J.; Stewart, T.G.; Felker, G.M.; Jayaweera, D.; Sulkowski, M.; Gentile, N.; Bramante, C.; et al. Fluvoxamine for Outpatient Treatment of COVID-19: A Decentralized, Placebo-Controlled, Randomized, Platform Clinical Trial. medRxiv 2022. [Google Scholar] [CrossRef]
- Bramante, C.T.; Huling, J.D.; Tignanelli, C.J.; Buse, J.B.; Liebovitz, D.M.; Nicklas, J.M.; Cohen, K.; Puskarich, M.A.; Belani, H.K.; Proper, J.L.; et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for COVID-19. N. Engl. J. Med. 2022, 387, 599–610. [Google Scholar] [CrossRef]
- Reis, G.; dos Santos Moreira Silva, E.A.; Medeiros Silva, D.C.; Thabane, L.; de Souza Campos, V.H.; Ferreira, T.S.; Quirino dos Santos, C.V.; Ribeiro Nogueira, A.M.; Figueiredo Guimaraes Almeida, A.P.; Cançado Monteiro Savassi, L.; et al. Oral Fluvoxamine with Inhaled Budesonide for Treatment of Early-Onset COVID-19: A Randomized Platform Trial. Ann. Intern. Med. 2023, 176, 667–675. [Google Scholar]
- Wang, H.; Wei, Y.; Hung, C.T.; Jiang, X.; Li, C.; Jia, K.M.; Leung, E.Y.M.; Yam, C.H.K.; Chow, T.Y.; Zhao, S.; et al. Chong. Relationship between Antidepressants and Severity of SARS-CoV-2 Omicron Infection: A Retrospective Cohort Study Using Real-World Data. Lancet Reg. Health-West. Pac. 2023, 34, 100716. [Google Scholar]
- Sidky, H.; Sahner, D.K.; Girvin, A.T.; Hotaling, N.; Michael, S.G.; Kurilla, M.G.; Gersing, K. Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19. medRxiv 2023. [Google Scholar] [CrossRef]
- Kornhuber, J.; Hoertel, N.; Gulbins, E. The acid sphingomyelinase/ceramide system in COVID-19. Mol. Psychiatry 2022, 27, 307–314. [Google Scholar] [CrossRef]
- Hoertel, N.; Sánchez-Rico, M.; Cougoule, C.; Gulbins, E.; Kornhuber, J.; Carpinteiro, A.; Becker, K.A.; Reiersen, A.M.; Lenze, E.J.; Seftel, D.; et al. Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: Current evidence and potential mechanisms. Mol. Psychiatry 2021, 26, 7098–7099. [Google Scholar] [CrossRef]
- Sukhatme, V.P.; Reiersen, A.M.; Vayttaden, S.J.; Sukhatme, V.V. Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19. Front. Pharmacol. 2021, 12, 652688. [Google Scholar]
- Recovery Collaborative Group. Colchicine in Patients Admitted to Hospital with COVID-19 (Recovery): A Randomised, Controlled, Open-Label, Platform Trial. Lancet Respir. Med. 2021, 9, 1419–1426. [Google Scholar] [CrossRef]
- Chen, J.; Ahn, S.; Wang, J.; Lu, Y.; Dalton, J.T.; Miller, D.D.; Li, W. Discovery of Novel 2-Aryl-4-benzoyl-imidazole (ABI-III) Analogues Targeting Tubulin Polymerization As Antiproliferative Agents. J. Med. Chem. 2012, 55, 7285–7289. [Google Scholar] [CrossRef] [Green Version]
- Wang, Q.; Arnst, K.E.; Wang, Y.; Kumar, G.K.; Ma, D.; White, S.W.; Miller, D.D.; Li, W.; Li, W. Structure-Guided Design, Synthesis, and Biological Evaluation of (2-(1H-Indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) Methanone (ABI-231) Analogues Targeting the Colchicine Binding Site in Tubulin. J. Med. Chem. 2019, 62, 6734–6750. [Google Scholar] [CrossRef]
- Barnette, K.G.; Gordon, M.S.; Rodriguez, D.; Bird, T.G.; Skolnick, A.; Schnaus, M.; Skarda, P.K.; Lobo, S.; Sprinz, E.; Arabadzhiev, G.; et al. Oral Sabizabulin for High-Risk, Hospitalized Adults with COVID-19: Interim Analysis. NEJM Évid. 2022, 1, 1–11. [Google Scholar] [CrossRef]
- Wang, R.; Xiao, H.; Guo, R.; Li, Y.; Shen, B. The role of C5a in acute lung injury induced by highly pathogenic viral infections. Emerg. Microbes Infect. 2015, 4, e28. [Google Scholar] [CrossRef]
- Carvelli, J.; Demaria, O.; Vély, F.; Batista, L.; Benmansour, N.C.; Fares, J.; Carpentier, S.; Thibult, M.-L.; Morel, A.; Remark, R.; et al. Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature 2020, 588, 146–150. [Google Scholar] [CrossRef]
- Vlaar, A.P.J.; Witzenrath, M.; van Paassen, P.; A Heunks, L.M.; Mourvillier, B.; de Bruin, S.; Lim, E.H.T.; Brouwer, M.C.; Tuinman, P.R.; Saraiva, J.F.K.; et al. Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir. Med. 2022, 10, 1137–1146. [Google Scholar] [CrossRef]
- Postler, T.S.; Peng, V.; Bhatt, D.M.; Ghosh, S. Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism. Sci. Rep. 2021, 11, 18721. [Google Scholar] [CrossRef]
- Xian, H.; Liu, Y.; Nilsson, A.R.; Gatchalian, R.; Crother, T.R.; Tourtellotte, W.G.; Zhang, Y.; Aleman-Muench, G.R.; Lewis, G.; Chen, W.; et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 2021, 54, 1463–1477.e11. [Google Scholar] [CrossRef]
- Cameron, A.R.; Morrison, V.L.; Levin, D.; Mohan, M.; Forteath, C.; Beall, C.; McNeilly, A.D.; Balfour, D.J.; Savinko, T.; Wong, A.K.; et al. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ. Res. 2016, 119, 652–665. [Google Scholar] [CrossRef] [Green Version]
- Justice, J.N.; Gubbi, S.; Kulkarni, A.; Bartley, J.M.; Kuchel, G.A.; Barzilai, N. A geroscience perspective on immune resilience and infectious diseases: A potential case for metformin. Geroscience 2021, 43, 1093–1112. [Google Scholar] [CrossRef]
- Kamyshnyi, O.; Matskevych, V.; Lenchuk, T.; Strilbytska, O.; Storey, K.; Lushchak, O. Metformin to decrease COVID-19 severity and mortality: Molecular mechanisms and therapeutic potential. Biomed. Pharmacother. 2021, 144, 112230. [Google Scholar] [CrossRef]
- Ganesh, A.; Randall, M.D. Does metformin affect outcomes in COVID-19 patients with new or pre-existing diabetes mellitus? A systematic review and meta-analysis. Br. J. Clin. Pharmacol. 2022, 88, 2642–2656. [Google Scholar] [CrossRef]
- Ibrahim, S.; Lowe, J.R.; Bramante, C.T.; Shah, S.; Klatt, N.R.; Sherwood, N.; Aronne, L.; Puskarich, M.; Tamariz, L.; Palacio, A.; et al. Metformin and COVID-19: Focused Review of Mechanisms and Current Literature Suggesting Benefit. Front. Endocrinol. 2021, 12, 587801. [Google Scholar] [CrossRef]
- Li, Y.; Yang, X.; Yan, P.; Sun, T.; Zeng, Z.; Li, S. Metformin in Patients With COVID-19: A Systematic Review and Meta-Analysis. Front. Med. 2021, 8, 704666. [Google Scholar] [CrossRef]
- Poly, T.N.; Islam, M.; Li, Y.-C.; Lin, M.-C.; Hsu, M.-H.; Wang, Y.-C. Metformin Use Is Associated with Decreased Mortality in COVID-19 Patients with Diabetes: Evidence from Retrospective Studies and Biological Mechanism. J. Clin. Med. 2021, 10, 3507. [Google Scholar] [CrossRef]
- Yang, W.; Sun, X.; Zhang, J.; Zhang, K. The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus. Diabetes Res. Clin. Pract. 2021, 178, 108977. [Google Scholar] [CrossRef]
- Bramante, C.T.; E Ingraham, N.; A Murray, T.; Marmor, S.; Hovertsen, S.; Gronski, J.; McNeil, C.; Feng, R.; Guzman, G.; Abdelwahab, N.; et al. Metformin and risk of mortality in patients hospitalised with COVID-19: A retrospective cohort analysis. Lancet Health Longev. 2020, 2, e34–e41. [Google Scholar] [CrossRef]
- Huang, I.; Lim, M.A.; Pranata, R. Diabetes Mellitus Is Associated with Increased Mortality and Severity of Disease in COVID-19 Pneumonia—A Systematic Review, Meta-Analysis, and Meta-Regression. Diabetes Metab. Syndr. 2020, 14, 395–403. [Google Scholar] [CrossRef]
- Simonnet, A.; Chetboun, M.; Poissy, J.; Raverdy, V.; Noulette, J.; Duhamel, A.; Labreuche, J.; Mathieu, D.; Pattou, F.; Jourdain, M.; et al. High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Requiring Invasive Mechanical Ventilation. Obesity (Silver Spring) 2020, 28, 1195–1199. [Google Scholar] [CrossRef] [Green Version]
- Reis, G.; Silva, E.A.D.S.M.; Silva, D.C.M.; Thabane, L.; Milagres, A.C.; Ferreira, T.S.; dos Santos, C.V.Q.; Neto, A.D.d.F.; Callegari, E.D.; Savassi, L.C.M.; et al. Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial. Lancet Reg. Health-Am. 2022, 6, 100142. [Google Scholar] [CrossRef]
- Bramante, C.; Buse, J.B.; Liebovitz, D.; Nicklas, J.; Puskarich, M.; Cohen, K.R.; Belani, H.; Anderson, B.; Huling, J.D.; Thompson, J.; et al. Outpatient Treatment of COVID-19 and Incidents of Post-COVID-19 over 10 Months: A Multi-Center, Randomised, Quadruple-Blind, Parallel-Group, Phase 3 Trial. Lancet Infect Dis. 2023, S1473–S3099. [Google Scholar]
- Ko, E.R.; Anstrom, K.J.; Panettieri, R.A., Jr.; Lachiewicz, A.M.; Maillo, M.; O’Halloran, J.; Boucher, C.; Smith, P.B.; McCarthy, M.W.; Segura Nunez, P.; et al. Abatacept for Treatment of Adults Hospitalized with Moderate or Severe COVID-19. medRxiv 2022. [Google Scholar] [CrossRef]
- Julia, A.; Bonafonte-Pardas, I.; Gómez, A.; Lopez-Lasanta, M.; Lopez-Corbeto, M.; Martinez-Mateu, S.H.; Lladós, J.; Rodriguez-Nunez, I.; Myers, R.M.; Marsal, S. Targeting of the Cd80/86 Proinflammatory Axis as a Therapeutic Strategy to Prevent Severe COVID-19. Sci. Rep. 2021, 11, 11462. [Google Scholar] [CrossRef]
- Yuen, C.-K.; Lam, J.-Y.; Wong, W.-M.; Mak, L.-F.; Wang, X.; Chu, H.; Cai, J.-P.; Jin, D.-Y.; To, K.K.-W.; Chan, J.F.-W.; et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg. Microbes Infect. 2020, 9, 1418–1428. [Google Scholar] [CrossRef]
- Schoggins, J.W.; Rice, C.M. Interferon-stimulated genes and their antiviral effector functions. Curr. Opin. Virol. 2011, 1, 519–525. [Google Scholar] [CrossRef]
- Park, A.; Iwasaki, A. Type I and Type Iii Interferons—Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe 2020, 27, 870–878. [Google Scholar] [CrossRef]
- Kaufmann, S.H.E.; Dorhoi, A.; Hotchkiss, R.S.; Bartenschlager, R. Host-directed therapies for bacterial and viral infections. Nat. Rev. Drug Discov. 2018, 17, 35–56. [Google Scholar] [CrossRef]
- Ivashkiv, L.B.; Donlin, L.T. Regulation of type I interferon responses. Nat. Rev. Immunol. 2014, 14, 36–49. [Google Scholar] [CrossRef] [Green Version]
- Davidson, S.; McCabe, T.M.; Crotta, S.; Gad, H.H.; Hessel, E.M.; Beinke, S. Ifnlambda Is a Potent Anti-Influenza Therapeutic without the Inflammatory Side Effects of Ifnalpha Treatment. EMBO Mol. Med. 2016, 8, 1099–1112. [Google Scholar] [CrossRef]
- Santer, D.M.; Li, D.; Ghosheh, Y.; Zahoor, M.A.; Prajapati, D.; Hansen, B.E.; Tyrrell, D.L.J.; Feld, J.J.; Gehring, A.J. Interferon-Lambda Treatment Accelerates SARS-CoV-2 Clearance Despite Age-Related Delays in the Induction of T Cell Immunity. Nat. Commun. 2022, 13, 6992. [Google Scholar] [CrossRef]
- Dijkman, R.; Verma, A.K.; Selvaraj, M.; Ghimire, R.; Gad, H.H.; Hartmann, R.; More, S.; Perlman, S.; Thiel, V.; Channappanavar, R. Effective Interferon Lambda Treatment Regimen to Control Lethal Mers-Cov Infection in Mice. J. Virol. 2022, 96, e0036422. [Google Scholar] [CrossRef]
- Reis, G.; Silva, E.A.M.; Silva, D.C.M.; Thabane, L.; Campos, V.H.; Ferreira, T.S.; Santos, C.V.; Nogueira, A.M.; Almeida, A.P.; Savassi, L.C.; et al. Early Treatment with Pegylated Interferon Lambda for COVID-19. N. Engl. J. Med. 2023, 388, 518–528. [Google Scholar] [CrossRef]
- Monk, P.D.; Marsden, R.J.; Tear, V.J.; Brookes, J.; Batten, T.N.; Mankowski, M.; Gabbay, F.J.; Davies, D.E.; Holgate, S.T.; Ho, L.P.; et al. Safety and Efficacy of Inhaled Nebulised Interferon Beta-1a (Sng001) for Treatment of SARS-CoV-2 Infection: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial. Lancet Respir. Med. 2021, 9, 196–206. [Google Scholar] [CrossRef]
- Rossignol, J.-F. Nitazoxanide: A first-in-class broad-spectrum antiviral agent. Antivir. Res. 2014, 110, 94–103. [Google Scholar] [CrossRef] [Green Version]
- Trabattoni, D.; Gnudi, F.; Ibba, S.V.; Saulle, I.; Agostini, S.; Masetti, M.; Biasin, M.; Rossignol, J.-F.; Clerici, M. Thiazolides Elicit Anti-Viral Innate Immunity and Reduce HIV Replication. Sci. Rep. 2016, 6, 27148. [Google Scholar] [CrossRef] [Green Version]
- Bharti, C.; Sharma, S.; Goswami, N.; Sharma, H.; Rabbani, S.; Kumar, S. Role of nitazoxanide as a repurposed drug in the treatment and management of various diseases. Drugs Today 2021, 57, 455–473. [Google Scholar] [CrossRef]
- Shakya, A.; Bhat, H.R.; Ghosh, S.K. Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent. Curr. Cancer Drug Targets 2018, 15, 201–213. [Google Scholar] [CrossRef]
- Rocco, P.R.; Silva, P.L.; Cruz, F.F.; Melo-Junior, M.A.C.; Tierno, P.F.; Moura, M.A.; De Oliveira, L.F.G.; Lima, C.C.; Dos Santos, E.A.; Junior, W.F.; et al. Early Use of Nitazoxanide in Mild COVID-19 Disease: Randomised, Placebo-Controlled Trial. Eur. Respir. J. 2021, 58, 2003725. [Google Scholar] [CrossRef]
- Blum, V.F.; Cimerman, S.; Hunter, J.R.; Tierno, P.; Lacerda, A.; Soeiro, A.; Cardoso, F.; Bellei, N.C.; Maricato, J.; Mantovani, N.; et al. Nitazoxanide superiority to placebo to treat moderate COVID-19–A Pilot prove of concept randomized double-blind clinical trial. Eclinicalmedicine 2021, 37, 100981. [Google Scholar] [CrossRef]
- Rocco, P.R.; Silva, P.L.; Cruz, F.F.; Tierno, P.F.; Rabello, E.; Junior, J.C.; Haag, F.; de Ávila, R.E.; da Silva, J.D.; Mamede, M.; et al. Nitazoxanide in Patients Hospitalized with COVID-19 Pneumonia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. Front. Med. 2022, 9, 844728. [Google Scholar] [CrossRef]
- Hong, S.K.; Kim, H.J.; Song, C.S.; Choi, I.S.; Lee, J.B.; Park, S.Y. Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. Int. Immunopharmacol. 2012, 13, 23–27. [Google Scholar] [CrossRef]
- Elazar, M.; Liu, M.; McKenna, S.A.; Liu, P.; Gehrig, E.A.; Puglisi, J.D.; Rossignol, J.; Glenn, J.S. The Anti-Hepatitis C Agent Nitazoxanide Induces Phosphorylation of Eukaryotic Initiation Factor 2α Via Protein Kinase Activated by Double-Stranded RNA Activation. Gastroenterology 2009, 137, 1827–1835. [Google Scholar] [CrossRef]
- Saxena, A. Drug targets for COVID-19 therapeutics: Ongoing global efforts. J. Biosci. 2020, 45, 87. [Google Scholar] [CrossRef]
- Papapanou, M.; Papoutsi, E.; Giannakas, T.; Katsaounou, P. Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19. J. Pers. Med. 2021, 11, 668. [Google Scholar] [CrossRef]
- White, K.M.; Rosales, R.; Yildiz, S.; Kehrer, T.; Miorin, L.; Moreno, E.; Jangra, S.; Uccellini, M.B.; Rathnasinghe, R.; Coughlan, L.; et al. Plitidepsin Has Potent Preclinical Efficacy against SARS-CoV-2 by Targeting the Host Protein Eef1a. Science 2021, 371, 926–931. [Google Scholar] [CrossRef]
- Varona, J.F.; Landete, P.; Lopez-Martin, J.A.; Estrada, V.; Paredes, R.; Guisado-Vasco, P.; de Orueta, L.F.; Torralba, M.; Fortún, J.; Vates, R.; et al. Plitidepsin Has a Positive Therapeutic Index in Adult Patients with COVID-19 Requiring Hospitalization. medRxiv 2021. [Google Scholar] [CrossRef]
- Abbas, W.; Kumar, A.; Herbein, G. The Eef1a Proteins: At the Crossroads of Oncogenesis, Apoptosis, and Viral Infections. Front. Oncol. 2015, 5, 75. [Google Scholar] [CrossRef] [Green Version]
- Li, D.; Wei, T.; Abbott, C.M.; Harrich, D. The Unexpected Roles of Eukaryotic Translation Elongation Factors in RNA Virus Replication and Pathogenesis. Microbiol. Mol. Biol. Rev. 2013, 77, 253–266. [Google Scholar] [CrossRef] [Green Version]
- Sammaibashi, S.; Yamayoshi, S.; Kawaoka, Y. Strain-Specific Contribution of Eukaryotic Elongation Factor 1 Gamma to the Translation of Influenza A Virus Proteins. Front. Microbiol. 2018, 9, 1446. [Google Scholar] [CrossRef] [Green Version]
- Snape, N.; Li, D.; Wei, T.; Jin, H.; Lor, M.; Rawle, D.J.; Spann, K.M.; Harrich, D. The eukaryotic translation elongation factor 1A regulation of actin stress fibers is important for infectious RSV production. Virol. J. 2018, 15, 182. [Google Scholar] [CrossRef] [Green Version]
- Davis, W.G.; Blackwell, J.L.; Shi, P.-Y.; Brinton, M.A. Interaction between the Cellular Protein eEF1A and the 3′-Terminal Stem-Loop of West Nile Virus Genomic RNA Facilitates Viral Minus-Strand RNA Synthesis. J. Virol. 2007, 81, 10172–10187. [Google Scholar] [CrossRef] [Green Version]
- Stebbing, J.; Krishnan, V.; de Bono, S.; Ottaviani, S.; Casalini, G.; Richardson, P.J.; Monteil, V.; Lauschke, V.M.; Mirazimi, A.; Youhanna, S.; et al. Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients. EMBO Mol. Med. 2020, 12, e12697. [Google Scholar] [CrossRef]
- Bekerman, E.; Neveu, G.; Shulla, A.; Brannan, J.; Pu, S.-Y.; Wang, S.; Xiao, F.; Barouch-Bentov, R.; Bakken, R.R.; Mateo, R.; et al. Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects. J. Clin. Investig. 2017, 127, 1338–1352. [Google Scholar] [CrossRef] [Green Version]
- Naghavi, M.H.; Walsh, D. Microtubule Regulation and Function during Virus Infection. J. Virol. 2017, 91, e00538-17. [Google Scholar] [CrossRef] [Green Version]
- Oliva, M.; Tosat-Bitrián, C.; Barrado-Gil, L.; Bonato, F.; Galindo, I.; Garaigorta, U.; Álvarez-Bernad, B.; París-Ogáyar, R.; Lu-cena-Agell, D.; Giménez-Abián, J.F.; et al. Effect of Clinically Used Microtubule Targeting Drugs on Viral Infection and Transport Function. Int. J. Mol. Sci. 2022, 23, 3448. [Google Scholar] [CrossRef]
- Coleman, C.M.; Sisk, J.M.; Mingo, R.M.; Nelson, E.A.; White, J.M.; Frieman, M.B. Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion. J. Virol. 2016, 90, 8924–8933. [Google Scholar] [CrossRef] [Green Version]
- Li, Z.; Peng, M.; Chen, P.; Liu, C.; Hu, A.; Zhang, Y.; Peng, J.; Liu, J.; Li, Y.; Li, W.; et al. Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry. Cell Metab. 2022, 34, 424–440.e7. [Google Scholar] [CrossRef]
- Strobelt, R.; Adler, J.; Paran, N.; Yahalom-Ronen, Y.; Melamed, S.; Politi, B.; Shulman, Z.; Schmiedel, D.; Shaul, Y. Imatinib Inhibits SARS-CoV-2 Infection by an Off-Target-Mechanism. Sci. Rep. 2022, 12, 5758. [Google Scholar] [CrossRef]
- Parthasarathy, H.; Tandel, D.; Siddiqui, A.H.; Harshan, K.H. Metformin Suppresses SARS-CoV-2 in Cell Culture. Virus Res. 2022, 323, 199010. [Google Scholar] [CrossRef]
- Farfan-Morales, C.N.; Cordero-Rivera, C.D.; Reyes-Ruiz, J.M.; Hurtado-Monzón, A.M.; Osuna-Ramos, J.F.; González-González, A.M.; De Jesús-González, L.A.; Palacios-Rápalo, S.N.; del Ángel, R.M. Anti-flavivirus Properties of Lipid-Lowering Drugs. Front. Physiol. 2021, 12, 749770. [Google Scholar] [CrossRef]
- Del Campo, J.A.; Garcia-Valdecasas, M.; Gil-Gomez, A.; Rojas, A.; Gallego, P.; Ampuero, J.; Gallego-Durán, R.; Pastor, H.; Grande, L.; Padillo, F.J.; et al. Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy. PLoS ONE 2018, 13, e0191805. [Google Scholar] [CrossRef] [Green Version]
- Najjar-Debbiny, R.; Gronich, N.; Weber, G.; Khoury, J.; Amar, M.; Stein, N.; Goldstein, L.H.; Saliba, W. Effectiveness of Paxlovid in Reducing Severe Coronavirus Disease 2019 and Mortality in High-Risk Patients. Clin. Infect. Dis. 2023, 76, e342–e349. [Google Scholar] [CrossRef]
- Hung, Y.P.; Lee, J.C.; Chiu, C.W.; Lee, C.C.; Tsai, P.J.; Hsu, I.L.; Ko, W.C. Oral Nirmatrelvir/Ritonavir Therapy for COVID-19: The Dawn in the Dark? Antibiotics 2022, 11, 220. [Google Scholar] [CrossRef]
- Lin, H.X.J.; Cho, S.; Aravamudan, V.M.; Sanda, H.Y.; Palraj, R.; Molton, J.S.; Venkatachalam, I. Remdesivir in Coronavirus Disease 2019 (COVID-19) treatment: A review of evidence. Infection 2021, 49, 401–410. [Google Scholar] [CrossRef]
- Warren, T.K.; Jordan, R.; Lo, M.K.; Ray, A.S.; Mackman, R.L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H.C.; et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016, 531, 381–385. [Google Scholar] [CrossRef] [Green Version]
- Higgs, E.S.; Gayedyu-Dennis, D.; Ii, W.A.F.; Nason, M.; Reilly, C.; Beavogui, A.H.; Aboulhab, J.; Nordwall, J.; Lobbo, P.; Wachekwa, I.; et al. PREVAIL IV: A Randomized, Double-Blind, 2-Phase, Phase 2 Trial of Remdesivir vs Placebo for Reduction of Ebola Virus RNA in the Semen of Male Survivors. Clin. Infect. Dis. 2021, 73, 1849–1856. [Google Scholar] [CrossRef]
- Malin, J.J.; Suárez, I.; Priesner, V.; Fätkenheuer, G.; Rybniker, J. Remdesivir against COVID-19 and Other Viral Diseases. Clin. Microbiol. Rev. 2020, 34, e00162-20. [Google Scholar] [CrossRef]
- Jayk Bernal, A.; Gomes da Silva, M.M.; Musungaie, D.B.; Kovalchuk, E.; Gonzalez, A.; Delos Reyes, V.; Martín-Quirós, A.; Caraco, Y.; Williams-Diaz, A.; Brown, M.L.; et al. Molnupiravir for Oral Treatment of COVID-19 in Nonhospitalized Patients. N. Engl. J. Med. 2022, 386, 509–520. [Google Scholar] [CrossRef]
- Painter, G.R.; Natchus, M.G.; Cohen, O.; Holman, W.; Painter, W.P. Developing a direct acting, orally available antiviral agent in a pandemic: The evolution of molnupiravir as a potential treatment for COVID-19. Curr. Opin. Virol. 2021, 50, 17–22. [Google Scholar] [CrossRef]
- Painter, W.P.; Holman, W.; Bush, J.A.; Almazedi, F.; Malik, H.; Eraut, N.C.; Morin, M.J.; Szewczyk, L.J.; Painter, G.R. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2. Antimicrob. Agents Chemother. 2021, 65, e02428-20. [Google Scholar] [CrossRef]
- Cox, R.M.; Wolf, J.D.; Plemper, R.K. Therapeutically Administered Ribonucleoside Analogue Mk-4482/Eidd-2801 Blocks SARS-CoV-2 Transmission in Ferrets. Nat. Microbiol. 2021, 6, 11–18. [Google Scholar] [CrossRef]
- Fang, F.C. Perspectives series: Host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J. Clin. Investig. 1997, 99, 2818–2825. [Google Scholar] [CrossRef] [Green Version]
- Regev-Shoshani, G.; Vimalanathan, S.; McMullin, B.; Road, J.; Av-Gay, Y.; Miller, C. Gaseous nitric oxide reduces influenza infectivity in vitro. Nitric Oxide 2013, 31, 48–53. [Google Scholar] [CrossRef]
- Åkerström, S.; Mousavi-Jazi, M.; Klingström, J.; Leijon, M.; Lundkvist, A.; Mirazimi, A. Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus. J. Virol. 2005, 79, 1966–1969. [Google Scholar] [CrossRef] [Green Version]
- Al Sulaiman, K.; Korayem, G.B.; Altebainawi, A.F.; Al Harbi, S.; Alissa, A.; Alharthi, A.; Kensara, R.; Alfahed, A.; Vishwakarma, R.; Al Haji, H.; et al. Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: A multicenter cohort study. Crit. Care 2022, 26, 304. [Google Scholar] [CrossRef]
- Longobardo, A.; Montanari, C.; Shulman, R.; Benhalim, S.; Singer, M.; Arulkumaran, N. Inhaled nitric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome. Br. J. Anaesth. 2020, 126, e44–e46. [Google Scholar] [CrossRef]
- Tandon, M.; Wu, W.; Moore, K.; Winchester, S.; Tu, Y.P.; Miller, C.; Kodgule, R.; Pendse, A.; Rangwala, S.; Joshi, S. SARS-CoV-2 Accelerated Clearance Using a Novel Nitric Oxide Nasal Spray (Nons) Treatment: A Randomized Trial. Lancet Reg. Health Southeast Asia 2022, 3, 100036. [Google Scholar] [CrossRef]
- Winchester, S.; John, S.; Jabbar, K.; John, I. Clinical efficacy of nitric oxide nasal spray (NONS) for the treatment of mild COVID-19 infection. J. Infect. 2021, 83, 237–279. [Google Scholar] [CrossRef]
- Fang, W.; Jiang, J.; Su, L.; Shu, T.; Liu, H.; Lai, S.; Ghiladi, R.A.; Wang, J. The role of NO in COVID-19 and potential therapeutic strategies. Free. Radic. Biol. Med. 2020, 163, 153–162. [Google Scholar] [CrossRef]
- Chiu, Y.-M.; Chen, D.-Y. Infection risk in patients undergoing treatment for inflammatory arthritis: Non-biologics versus biologics. Expert Rev. Clin. Immunol. 2020, 16, 207–228. [Google Scholar] [CrossRef]
- Murdaca, G.; Negrini, S.; Pellecchio, M.; Greco, M.; Schiavi, C.; Giusti, F.; Puppo, F. Update upon the infection risk in patients receiving TNF alpha inhibitors. Expert Opin. Drug Saf. 2019, 18, 219–229. [Google Scholar] [CrossRef]
- Levy, Y.; Vagima, Y.; Tidhar, A.; Zauberman, A.; Aftalion, M.; Gur, D.; Fogel, I.; Chitlaru, T.; Flashner, Y.; Mamroud, E. Adjunctive Corticosteroid Treatment against Yersinia Pestis Improves Bacterial Clearance, Immunopathology, and Survival in the Mouse Model of Bubonic Plague. J. Infect. Dis. 2016, 214, 970–977. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Crane, S.D.; Banerjee, S.K.; Pechous, R.D. Treatment with Fluticasone Propionate Increases Antibiotic Efficacy during Treatment of Late-Stage Primary Pneumonic Plague. Antimicrob. Agents Chemother. 2022, 66, e0127521. [Google Scholar] [CrossRef] [PubMed]
- Gal, Y.; Mazor, O.; Alcalay, R.; Seliger, N.; Aftalion, M.; Sapoznikov, A.; Falach, R.; Kronman, C.; Sabo, T. Antibody/doxycycline combined therapy for pulmonary ricinosis: Attenuation of inflammation improves survival of ricin-intoxicated mice. Toxicol. Rep. 2014, 1, 496–504. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lindauer, M.L.; Wong, J.; Iwakura, Y.; Magun, B.E. Pulmonary Inflammation Triggered by Ricin Toxin Requires Macrophages and IL-1 Signaling. J. Immunol. 2009, 183, 1419–1426. [Google Scholar] [CrossRef] [Green Version]
- Pandey, P.; Al Rumaih, Z.; Kels, M.J.T.; Ng, E.; Kc, R.; Chaudhri, G.; Karupiah, G. Targeting Ectromelia Virus and Tnf/Nf-Kappab or Stat3 Signaling for Effective Treatment of Viral Pneumonia. Proc. Natl. Acad. Sci. USA 2022, 119, e2112725119. [Google Scholar] [CrossRef]
- Yu, J.-W.; Sun, L.-J.; Zhao, Y.-H.; Kang, P.; Yan, B.-Z. The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance. Int. J. Infect. Dis. 2012, 16, e436–e441. [Google Scholar] [CrossRef] [Green Version]
- Guo, T.; Sun, X.; Yang, J.; Yang, L.; Li, M.; Wang, Y.; Jiao, H.; Li, G. Metformin reverse minocycline to inhibit minocycline-resistant Acinetobacter baumannii by destroy the outer membrane and enhance membrane potential in vitro. BMC Microbiol. 2022, 22, 215. [Google Scholar] [CrossRef]
- Farfan-Morales, C.N.; Cordero-Rivera, C.D.; Osuna-Ramos, J.F.; Monroy-Muñoz, I.E.; De Jesús-González, L.A.; Muñoz-Medina, J.E.; Hurtado-Monzón, A.M.; Reyes-Ruiz, J.M.; del Ángel, R.M. The antiviral effect of metformin on zika and dengue virus infection. Sci. Rep. 2021, 11, 8743. [Google Scholar] [CrossRef]
- de Sousa, A.K.; Rocha, J.E.; de Souza, T.G.; de Freitas, T.S.; Ribeiro-Filho, J.; Coutinho, H.D.M. New Roles of Fluoxetine in Pharmacology: Antibacterial Effect and Modulation of Antibiotic Activity. Microb. Pathog. 2018, 123, 368–371. [Google Scholar] [CrossRef]
- Kummer, S.; Lander, A.; Goretzko, J.; Kirchoff, N.; Rescher, U.; Schloer, S. Pharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection in vitro. Emerg. Microbes Infect. 2022, 11, 195–207. [Google Scholar] [CrossRef]
- Kaul, G.; Akhir, A.; Shukla, M.; Rawat, K.S.; Sharma, C.P.; Sangu, K.G.; Rode, H.B.; Goel, A.; Chopra, S. Nitazoxanide potentiates linezolid against linezolid-resistant Staphylococcus aureus in vitro and in vivo. J. Antimicrob. Chemother. 2022, 77, 2456–2460. [Google Scholar] [CrossRef] [PubMed]
- Rossignol, J.-F. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J. Infect. Public Health 2016, 9, 227–230. [Google Scholar] [CrossRef] [Green Version]
- Raghuvanshi, R.; Bharate, S.B. Recent Developments in the Use of Kinase Inhibitors for Management of Viral Infections. J. Med. Chem. 2022, 65, 893–921. [Google Scholar] [CrossRef]
- Khani, E.; Shahrabi, M.; Rezaei, H.; Pourkarim, F.; Afsharirad, H.; Solduzian, M. Current evidence on the use of anakinra in COVID-19. Int. Immunopharmacol. 2022, 111, 109075. [Google Scholar] [CrossRef] [PubMed]
- Shaw, T.D.; Krasnodembskaya, A.D.; Schroeder, G.N.; Zumla, A.; Maeurer, M.; O’kane, C.M. Mesenchymal Stromal Cells: An Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases. Clin. Microbiol. Rev. 2021, 34, e0006421. [Google Scholar] [CrossRef]
- Chen, L.; Qu, J.; Kalyani, F.S.; Zhang, Q.; Fan, L.; Fang, Y.; Li, Y.; Xiang, C. Mesenchymal stem cell-based treatments for COVID-19: Status and future perspectives for clinical applications. Cell Mol. Life Sci. 2022, 79, 142. [Google Scholar] [CrossRef] [PubMed]
- Backer, V.; Sjöbring, U.; Sonne, J.; Weiss, A.; Hostrup, M.; Johansen, H.K.; Becker, V.; Sonne, D.P.; Balchen, T.; Jellingsø, M.; et al. A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19. Lancet Reg. Health-Eur. 2021, 4, 100084. [Google Scholar] [CrossRef]
Drug Class | Drug | Main Clinical Indication | Anti-COVID-19 Mechanism | Clinical Phase (COVID-19) [#Clinical Trial] | COVID-19 Indication |
---|---|---|---|---|---|
Steroids | Dexamethasone | Inflammatory and Autoimmune diseases | Anti-inflammatory | Recommended by the COVID-19 Treatment Guidelines Panel [NCT04381936] | hospitalized patients who require supplemental oxygen |
Budesonide | Airway diseases | 2 [NCT04416399] | mild–moderate COVID-19 patients | ||
Anti-cytokines | Tocilizumab | RA | Anti-IL-6 receptor | Approved [NCT04381936] | hospitalized patients above 2 years of age receiving systemic corticosteroids and requiring supplemental oxygen, NIMV or IMV, or ECMO |
Sarilumab | RA | Anti-IL-6 receptor | Recommended by the COVID-19 Treatment Guidelines Panel [NCT04315298; NCT02735707; NCT04327388] | recommended only when Tocilizumab is not available or feasible to use | |
Anakinra | RA | Recombinant IL-1 receptor antagonist | EUA [NCT04318366; NCT04357366; NCT04680949; CRD42020221491] | hospitalized adults with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma suPAR | |
Infliximab | Autoimmune diseases (Arthritis, IBD) | Anti-TNFα | 3 [NCT04593940] | moderate or severe condition in combination with steroids or Remdesivir | |
Lenzilumab | Hematologic malignancies | Anti-GM-CSF | 3 [NCT04351152; NCT04583969] | critically ill patients without “cytokine storm” or IMV, also treated with Remdesivir and/or steroids * | |
Otilimab | Autoimmune diseases | Anti-GM-CSF | 2 [NCT04376684] | a partial positive trend in patients above 70 years of age with systemic inflammation ** | |
Kinase inhibitors | Baricitinib *** | RA | JAK1/2 inhibitor | EUA [NCT04401579; NCT04640168] | hospitalized patients requiring supplemental oxygen, IMV, or ECMO in combination with Remdesivir |
Tofacitinib *** | RA | JAK1/3 inhibitor | 3 [NCT04469114] | recommended only when Baricitinib is not available or feasible to use | |
Imatinib *** | CML | Abl kinase inhibitor | [EudraCT 2020-001236-10] | hospitalized patients who require noninvasive oxygen support | |
SSRIs | Fluoxetine/ Fluvoxamine *** | Depressive and Anxiety disorders | ASM inhibitors S1Rs agonists Anti-inflammatory Anticoagulant | 2–3 [NCT04342663; NCT04727424; NCT05890586; NCT04510194] | early stage, non-hospitalized patients |
Microtubule disruptors | Sabizabulin *** | Prostate cancer | Anti-inflammatory | 3 [NCT04842747] | moderately to severely ill patients (with a high risk of ARDS and death) |
Complement inhibitors | Vilobelimab | COVID-19 | Anti-C5 mAb | EUA [NCT04333420] | hospitalized adults, initiated within 48 h of receiving IMV or ECMO |
Biguanide anti-hyperglycemic | Metformin *** | T2DM | Anti-inflammatory autophagy | 3 [NCT04510194; NCT04727424] | early outpatient treatment (women with T2DM or obesity) |
CTLA-4 analogs | Abatacept | RA | Anti-inflammatory | 3 [NCT04593940] | moderate or severe |
Antiviral Mechanism | Drug | Main Clinical Indication | Cellular Antiviral Target | Clinical Phase (COVID-19) [#Clinical Trial] | COVID-19 Indication |
---|---|---|---|---|---|
Immune response stimulation | Pegylated IFNλ-1a | Antiviral | N/A | Phase 3 [NCT04727424] | non-hospitalized patients |
IFN β-1a * | Antiviral | N/A | Phase 2 [NCT04385095] | hospitalized patients | |
Nitazoxanide ** | anti-parasitic | N/A | Phase 2 [NCT04552483; NCT04348409; NCT04561219] | mild hospitalized patients | |
Disruption of cellular mechanisms involved in viral life cycle and survival | Plitidepsin | Multiple Myeloma | eEF1A | Phase 3 [NCT04784559] | adult hospitalized patients with moderate COVID-19 infection (in combination with Dexamethasone) |
Baricitinib ** | RA | NAKs | EUA [NCT04401579; NCT04640168] | hospitalized patients requiring supplemental oxygen, IMV, or ECMO in combination with Remdesivir | |
Sabizabulin *** | Prostate cancer | MT inhibitor | Phase 3 [NCT04842747] | moderately to severely ill patients (with a high risk of ARDS and death) | |
Imatinib *** | CML | ACE2 | [EudraCT 2020–001236–10] | hospitalized patients who require noninvasive oxygen support | |
Metformin *** | T2DM | AMPK | Phase 3 [NCT04510194; NCT04727424] | early outpatient treatment (women with T2DM or obesity) |
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Dechtman, I.-D.; Ankory, R.; Sokolinsky, K.; Krasner, E.; Weiss, L.; Gal, Y. Clinically Evaluated COVID-19 Drugs with Therapeutic Potential for Biological Warfare Agents. Microorganisms 2023, 11, 1577. https://doi.org/10.3390/microorganisms11061577
Dechtman I-D, Ankory R, Sokolinsky K, Krasner E, Weiss L, Gal Y. Clinically Evaluated COVID-19 Drugs with Therapeutic Potential for Biological Warfare Agents. Microorganisms. 2023; 11(6):1577. https://doi.org/10.3390/microorganisms11061577
Chicago/Turabian StyleDechtman, Ido-David, Ran Ankory, Keren Sokolinsky, Esther Krasner, Libby Weiss, and Yoav Gal. 2023. "Clinically Evaluated COVID-19 Drugs with Therapeutic Potential for Biological Warfare Agents" Microorganisms 11, no. 6: 1577. https://doi.org/10.3390/microorganisms11061577
APA StyleDechtman, I.-D., Ankory, R., Sokolinsky, K., Krasner, E., Weiss, L., & Gal, Y. (2023). Clinically Evaluated COVID-19 Drugs with Therapeutic Potential for Biological Warfare Agents. Microorganisms, 11(6), 1577. https://doi.org/10.3390/microorganisms11061577