Abstract
SARS-CoV-2 infection causes COVID-19, which has emerged as a health emergency worldwide. SARS-CoV-2 infects cells by binding to ACE2 receptors and enters into the cytoplasm following its escape from endolysosomes. Once in the cytoplasm, the virus replicates and eventually causes various pathological conditions including acute respiratory distress syndrome (ARDS) that is caused by pro-inflammatory cytokine storms. Thus, endolysosomes and cytokine storms are important therapeutic targets to suppress SARS-CoV-2 infection and COVID-19. Here, we discuss therapeutic targets of SARS-CoV-2 infection and available drugs that could be helpful in the suppression of the SARS-CoV-2 infection and pathological condition COVID-19. The urgency of the COVID-19 pandemic precludes the development of new drugs and increased focus on drug repurposing might provide the quickest way to finding effective medicines.
Keywords
SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2), COVID-19 (Coronavirus Infectious Disease-19), Endolysosomes, ARDS (Acute Respiratory Distress Syndrome), Cytokine Storm
Introduction
The high fatality rate and rapidly increasing case numbers of COVID-19 have posed an urgent global health emergency. Contributing to infectivity and confounding containment efforts are large numbers of asymptomatic cases. Currently 208 million people have been infected with SARS-CoV-2 and over 4 million people have died worldwide from COVID-19; infectivity rates and numbers of deaths are particularly high in the USA [1]. This pandemic and health emergency highlights the need for identifying quickly effective therapeutic strategies. However, safe and effective new antiviral drugs usually take more than a decade to develop and therefore drug repurposing might be a better approach.
The SARS-CoV-2 virus has several potential targets against which novel drugs may be developed to suppress viral replication including blocking endocytosis of the virus into cells, viral escape from endolysosomes into the cytoplasm, blocking RNA replication and transcription, inhibiting translation and proteolytic processing of viral proteins, and blocking virion assembly and release from infected cells [2-8]. Suppression of virus-induced cytokine storms can suppress pathological conditions in infected individuals [4,9,10]. Here, we focus attention on the involvement of endolysosomes in SARS-CoV-2 infection and the role that cytokine storms play in the development of COVID-19.
Endolysosomes
Endosomes and lysosomes (endolysosomes) are acidic organelles [11-13]; a critical feature that is regulated by lysosomes-associated proteins and ion channels including vacuolar-ATPase (v-ATPase) [14-16], two pore channels (TPCs) [17], big-potassium channels (BK) [18], and mucolipin-1 [18]. Endolysosomes play crucial roles in regulating cellular processes like cell cycles and death, metabolism, immune responses and antigen presentation, and membrane trafficking and signaling [19-24]. Endolysosomes have also been implicated in a number of pathological conditions as diverse as cancer, neurological disorders, and viral infections [19,20,24-26]. Different types of viruses use endolysosomes to enter into and infect cells [27-31]. SARS-CoV-2 is endocytosed and then is released into the cytoplasm where it replicates [2,5,32], however much work is still needed to understand better how the virus escapes the endolysosome degradation pathway.
Cytokine storms
Cytokine storms occur when there is an overproduction of pro-inflammatory cytokines; a consequence of SARS-CoV-2 infection that disturbs negative feedback regulatory mechanisms of the immune system [33-36]. High levels of pro-inflammatory cytokines are further enhanced because of positive feedback influences on other immune cells which are recruited to sites of inflammation [37,38]. Various cytokines are involved in developing cytokine storms including tumor necrosis factor (TNF), interleukin (IL), colony-stimulating factor (CSF), and interferon (IFN). These virus-induced cytokine storms can lead to the development of ARDS, a systemic inflammatory response that can result in multiple organ failure [38-40]. Thus, cytokine storms are important targets for therapeutic intervenstion. In Table 1 we list therapeutic drugs that might be studied further for use against COVID-19 and target endolysosomes and cytokine storms.
|
Class |
Therapeutics Candidates |
Potential Mechanism: Mode of Action |
|
Receptor or ligand-based antibody or peptide [49,50] Abelson kinase inhibitors [51] |
Vaccine based on coronavirus spike proteins fusion peptides (EK1C4) |
Inhibition of virus-host membrane fusion |
|
Cathepsin L inhibitors [52,59,67] Cathepsin K inhibitor [68] Cathepsin D [68] Endocytosis antagonist [62,63] Na+/K+-ATPase inhibitors [64,65] Quinoline [71,72] Adenosine triphosphate analog [98] Pyrazine carboxamide [97] Antihelmintic [99] |
Camostat, Z-FY (t-Bu)-DMK, K11777, and Teicoplanin MD28170 and ONO5335 Chloropromazine, triflupromazine Bufalin and Quabain CQ and HCQ Remdesivir Favipiravir Antihelmintic |
Inhibition of virus entry Inhibition of virus entry Inhibition of virus entry Inhibition of virus entry Inhibition of virus entry Inhibition of virus entry Reduction of virus replication Reduction of virus replication Reduction of virus replication |
|
Natural hormone supplements [133] Vitamin D [110,111] Steroid hormone [6,120,122] Polyamines [134] Flavone glycoside [135] Stilbenod [7] Beta-hydroxybutyrate, acetone [136] Disaccharide [7] Flavone [137] Flavone [137] Chalconoid [137] Polyphenol [7] Flavanone [7] STA-5326 [68] Bis-benzylisoquinoline [68] Inhibitor of cholesterol trafficking [91] Tricyclic antidepressant (TCA) [92] Anti-fungus [138] Anti-neoplastic compound [93] |
Melatonin Calcitriol Estradiol Spermidine and Spermine Baicalin Resveratrol Ketone bodies Trehalose Apigenin Wogonin Butein Curcumin Naringenin Apilimod Hanfangchin A U1866A Imipramine Itraconazole, Posaconazole Cepharanthine |
Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer Anti-inflammatory and autophagy inducer TPCs inhibitor PIKFyve Kinase inhibitor TPCs inhibitor NPC1 inhibitor NPC1 inhibitor NPC1 inhibitor TPCs and NPC1 inhibitor |
|
Exogenous RAS Modulators [45,139] AT1R blocker (ARB) [139] Interferon III [140] |
Recombinant ACE2, Ang (1-7), Irbesartan, Iosartan Pegylated INF-λ |
Anti-hypertensive Aung (1-7), anti-inflammatory effects Anti-hypertensive Ang (1-7), anti-inflammatory effects Anti-inflammatory and enhance defense of respiration epithelium |
|
Type-1 interferon [141,142] Tetracycline antibiotic [119,143] Glucocorticoid [122] IL-17 inhibitor [144] IL-6 inhibitor [130] TNF inhibitor [128] JAK inhibitor [145] |
Interferon Doxycycline Dexamethasone Sekukinumab, Broadalumab Tocilzumab, Siltuximab Etanercept Tofacitinib |
Anti-viral and anti-inflammatory Anti-inflammatory response Anti-inflammatory response Anti-inflammatory response Anti-inflammatory response Anti-inflammatory response Anti-inflammatory response |
Targeting Endolysosomes for Suppressing SARS-CoV-2 Infection
The endolysosome pathway may be a therapeutic target to suppress SARS-CoV-2 infection and COVID-19 [5,41]. The involvement of the endolysosome system starts with SARS-CoV-2 binding to receptors on cell membranes and this is followed by entry into and pH-dependent escape from endolysosomes [5,41]. The spike protein of SARS-CoV-2 is essential for viral entry into cells governed by ACE2 receptor-mediated endocytosis and priming via cellular proteases; all are protected from host immune surveillance [42-44]. Vaccines and antibody-based therapies are challenged by the high binding capacity of the receptors and by ability of spike proteins to escape from host immune surveillance.
Recombinant protein and peptide-based therapies could successfully block virus entry and pathogenic conditions in COVID-19 patients. Indeed, recombinant human ACE2 (APNO1, rhACE2) is currently being developed as a therapeutic target to treat pulmonary arterial hypertension and ARDS [45,46]. Recombinant human ACE2 (rhACE2) protein reduced virus entry into human cell-derived organoids probably acting as a decoy for virus binding [47]. Additional sites for intervention against viral infection include the spike S2 stalk that contains HR1 and HR2 hydrophobic regions; stable six-helix-bundle (6-HB) structures that fuse the virus with host cell membranes. Hence, fusion peptides against HR1 and HR2 hydrophobic regions of spike S2 stalk could be barriers to the virus infection. A lipopeptide derived from EK1, EK1C4, inhibited in nanomolar concentrations SARS-CoV-2 pseudovirus infection and spike protein-mediated membrane fusion [48-50]. Additionally, abelson kinase (ABL) inhibitors (imatinib, dasatinib) blocked cell-fusion of SARS-CoV and MARS-CoV required for virus entry into cells and may similarly protect against SARS-CoV-2 [51].
Following endocytosis, successful viral entry is achieved by proteolytic cleavage of spike proteins catalyzed by the cellular proteases furin, TMPRSS2, and cathepsins; both pH-independently and -dependently [52-59]. Several compounds may block viral infection by restricting endocytosis and proteolytic processing of the spike protein including chlorpromazine, triflupromazine, bufalin & ouabain and camostat mesylate, Z-FY (t-Bu)-DMK, K11777, teicoplanin, MD28170, ONO5335, CQ & HCQ, and lopinavir [59-61].
Chlorpromazine, an anti-schizophrenia drug, inhibits clathrin-mediated endocytosis of the coronaviruses MHV, MERS-CoV, and SARS-CoV [62,63]. Similarly, Na+/K+-ATPase pump-based inhibitors bufalin and ouabain restricted MERS-CoV infection by inhibiting clathrin-mediated endocytosis [64,65].
Camostat mesylate, an inhibitor of TMPRSS2, is used to treat chronic pancreatitis and it has been shown to suppress SARS-CoV-2 infection in human cells and in mice [59,66]. Clinical trials have begun in Germany and the Netherlands with camostat for COVID-19. Because cathepsins are important for pH-dependent SARS-CoV-2 entry cathepsin L, B, and K inhibitors Z-FY (t-Bu)-DMK, K11777, Teicoplanin, MD28170, and ONO5335 may potentially suppress SARS-CoV-2 infection [67, 68].
CQ and HCQ, anti-malarial drugs that affect endolysosome function, block autophagic flux by deacidifying endolysosomes and inhibit SARS-CoV-2 virus infection in cellular models [69,70]. Both drugs are hyped as prophylaxis drugs against COVID-19; however, their prophylactic effects are not clinically established [71,72]. Both drugs have potential risks of arrhythmia, retinopathy, and reduced antiviral type-1 interferon responses by deactivating RNA sensors (TLR) in endolysosomes [73-78]. Co-administration of IFN-I and HCQ may suppress COVID-19 in patients [79,80] and IFN-I may alleviate HCQ-induced risks by enhancing antiviral responses and autophagy [79,80]. IFN-I-induced autophagy may restrict virus replication by degrading it in lysosomes and potentially enhance antiviral immune responses [34,81].
Endolysosome-associated ion channels (TPCs, NPC1, and v-ATPase) regulate endolysosome pH and thereby affect SARS-CoV-2 infection. TPCs are involved in the entry and trafficking of SARS-CoV-2, MERS-CoV, and Ebola virus [82-84]; the TPC inhibitors tetrandrine, Ned-19 [82], and hanfangchin A significantly inhibited the entry and trafficking of viruses in host cells [68]. Furthermore, apilimod and vaculin-1 restricted SARS-CoV-2 infection by reducing PIKfyve enzyme activity [82,85]; PIKfyve is a regulator of PI (3,5) P2, an endogenous activator of TPCs [86]. Apilimod has antagonistic effects on SARS-CoV-2 infection in primary human lung explants and in human iPSC-derived pneumocyte-like cells [68]. Interestingly, apilimod has also been shown to have a broad-spectrum antiviral activity.
Niemann-Pick disease type C1 (NPC1), an endolysosome-resident protein, is involved in cellular lipid trafficking and the entry of the Ebola virus, MERS-CoV, and SARS-CoV [30,87-90]. NPC1 inhibitors, U1866A and imipramine have broad antiviral activity presumably by deacidifying endolysosomes and accumulating lipids in endolysosomes [91,92]. In addition, cepharanthine, an inhibitor of TPC2 and NPC1, has antiviral activity [93]. Thus, TPCs and NPC1 might attract attention as possible targets to suppress SARS-CoV-2 infection and COVID-19.
v-ATPase is one of the major mechanisms by which pH is regulated in endolysosomes. Endolysosome deacidification by BafA1 inhibits coronavirus infections by targeting the v-ATPase pump [52,59,94]. The SARS-CoV 3CLpro protease de-acidifies endolysosomes by direct interaction with the G1 subunit of v-ATPase and blocks degradation of viral factors [95] thereby enhancing virus replication. Notably, endolysosome acidification may restrict coronavirus infections by blocking the escape of viral RNA to the cytosol, promoting viral degradation in lysosomes, and enhancing autophagy-mediated antiviral responses. Regardless, several compounds acidify endolysosomes and enhance autophagy (Table 1) and might be tested for their ability to suppress SARS-CoV-2 infection.
After SARS-CoV-2 is uncoated and escapes from endolysosomes, the virus is replicated, translated, assembled into new virion particles, and released from infected cells to affect bystander cells. During replication, translated polypeptides are then subjected to autoproteolysis to generate various viral proteins including proteases and RdRp (RNA-dependent RNA polymerase), which could be excellent therapeutic targets because of their crucial roles in virus replication [96]. RdRP plays a vital role in replicating and transcribing viral RNA, making it a suitable and clear target for suppressing virus replication. Several broad-spectrum inhibitors of RdRp including Favipiravir and Remdesivir are either in clinical trials or are approved already for treating infected people [69,97,98]. Both drugs have promising effects against SARS-CoV-2 infection and COVID-19. Additionally, an in vitro study using ivermectin, an anti-parasitic drug, showed antiviral effects against SARS-CoV-2; there was reduced mortality rates possibly due to suppression of cytokine storms [99,100].
Suppressing COVID-19 by targetting cytokine storms: Cytokine storms in COVID-19 patients induces critical pathological conditions by damaging host organs [33,34]. Various treatments may suppress cytokine storms including recombinant ACE2 protein (exogenous RAS modulator) [101], exogenous Ang (1-7) [102], ACE inhibitors and AT1R blockers (irbesartan and losartan) to reduce the proinflammatory effects of Ang II [103], early treatment of type I-interferon (IFN-I) [104], pegylated IFN-lambda [105], and IFN-a2b [106]; protective effects have been observed with lung epithelial cells or upper respiratory tract. Other drugs (melatonin and vitamin D, doxycycline, corticosteroids, anti-TNF-a, IL-6, IL-17, JNK, inhibitors) will be discussed in later sections.
Melatonin has protective effects on vascular endothelial cells and lung tissue by suppressing MMP-9 and IL-6, VEGF, and TNF-α [107,108]. Vitamin D (calcitriol) reduces toll-like receptor-induced cytokine storms; lower plasma levels of vitamin D have been noted in SARS-CoV-2 infected patients and they have a higher risk of hospitalization [109,110]. Vitamin D also attenuated virus-induced cytopathic effects in human respiratory epithelial cells [111]. COVID-19 disease progression is slower in black individuals with high levels of vitamin D, however supplementation with vitamin D did not reduce the severity of COVID-19 compared with placebo [112,113]. Co-administration of vitamin D and melatonin could provide prophylactic protection against COVID-19 [114] because both are inducers of autophagy [115,116].
Doxycycline, a broad-spectrum antibiotic, has protective effects on dengue hemorrhagic fever by suppressing cytokine storms and reducing lymphocyte neutrophils' infiltration of inflamed tissues [117,118]. Also, doxycycline recovered and reduced disease progression in mild-to-moderate COVID-19 patients with ivermectin treatment [119].
Corticosteroids are generally used to suppress inflammation. However, the duration and timing of these drugs is crucial in the context of COVID-19; early corticosteroid treatment was associated with a high viral load [120]. Steroid administration may be beneficial during cytokine storms and ARDS in COVID-19 patients [121]. Dexamethasone, a corticosteroid, has reduced the mortality rate in COVID-19 patients requiring oxygen with or without invasive ventilation. However, dexamethasone could not reduce mortality risk in patients who did not need respiratory support [122]. The co-administration of tocilizumab and corticosteroids has shown protective effects in non-intubated COVID-19 patients [123]. Estradiol has protective effects in women with SARS-CoV-2 infection by different possible mechanisms [6,124].
Several therapeutic targets are mentioned in Table 1. Therapeutic agents used against cytokine storms include TNF-α inhibitors (Etanercept), IL-6 inhibitors (Tocilizumab, Siltuximab) [125], IL-17 inhibitors (Broadalumab, Sekukinumab) [126], and JNK inhibitors (Fedratinib, Tofacitinib) [127] (Table 1). Etanercept, a TNF-α inhibitor, decreased the risk of developing COVID-19 [128]; thus, it was proposed as a potential first-line choice in SARS-CoV-2 infection based on limited immunogenicity, short half-life, and safety considerations [129]. However, contradictory reports are available with anti-inflammatory drugs related to COVID-19 [130-132].
Conclusion
The pandemic caused by SARS-CoV-2 infection seriously threatens social-economic development and public health globally even though effective vaccines are becoming increasingly available. However, new variants of SARS-CoV-2 have emerged under selection pressure in different countries; even recently, double mutant strains (like B.1.617) have also emerged. Moreover, mutant strains of SARS-CoV-2 may escape available neutralizing antibodies and pose a new challenge in developing novel therapeutic drugs and vaccines. As suggested, several natural compounds and drugs are currently available for safe use, and randomized, blinded, and controlled clinical trials could test whether these drugs can be repurposed to treat SARS-CoV-2 infection.
Conflict of Interest
No conflict of Interest
Author contribution
All authors are equally contributed.
Funding
This work was partly supported by NIH grants; RO1MH119000, 2R01NS065957 and 2R01DA032444.
References
2. Guy RK, DiPaola RS, Romanelli F, Dutch RE. Rapid repurposing of drugs for COVID-19. Science. 2020 May 22;368(6493):829-30.
3. Poduri R, Joshi G, Jagadeesh G. Drugs targeting various stages of the SARS-CoV-2 life cycle: exploring promising drugs for the treatment of Covid-19. Cellular Signalling. 2020 Oct 1;74:109721.
4. Hussman JP. Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention. Frontiers in Pharmacology. 2020 Jul 29;11:1169.
5. Khan N, Chen X, Geiger JD. Role of endolysosomes in severe acute respiratory syndrome coronavirus-2 infection and coronavirus disease 2019 pathogenesis: implications for potential treatments. Frontiers in Pharmacology. 2020 Oct 29;11:1739.
6. Khan N. Possible protective role of 17β-estradiol against COVID-19. Journal of Allergy and Infectious Diseases. 2020;1(2):38.
7. Khan N, Chen X, Geiger JD. Possible Therapeutic Use of Natural Compounds Against COVID-19. Journal of Cellular Signaling. 2021;2(1):63.
8. Khan N. mTOR: A possible therapeutic target against SARS-CoV-2 infection. Archives of Stem Cell and Therapy. 2021;2(1):5-7.
9. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LF. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology. 2020 Jun;20(6):363-74.
10. Geiger JD, Khan N, Murugan M, Boison D. Possible role of adenosine in COVID-19 pathogenesis and therapeutic opportunities. Frontiers in Pharmacology. 2020;11.
11. Luzio, J.P., Sally R. Gray, and Nicholas A. Bright, Endosome–lysosome fusion. Biochemical Society Transactions. 2010:38(6): 1413-1416.
12. Luzio JP, Pryor PR, Bright NA. Lysosomes: fusion and function. Nature reviews Molecular Cell Biology. 2007 Aug;8(8):622-32.
13. Mullock BM, Bright NA, Fearon CW, Gray SR, Luzio J. Fusion of lysosomes with late endosomes produces a hybrid organelle of intermediate density and is NSF dependent. The Journal of Cell Biology. 1998 Feb 9;140(3):591-601.
14. Colacurcio DJ, Nixon RA. Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Research Reviews. 2016 Dec 1;32:75-88.
15. Collins MP, Forgac M. Regulation of V-ATPase assembly in nutrient sensing and function of V-ATPases in breast cancer metastasis. Frontiers in Physiology. 2018 Jul 13;9:902.
16. Halcrow PW, Khan N, Datta G, Ohm JE, Chen X, Geiger JD. Importance of measuring endolysosome, cytosolic, and extracellular pH in understanding the pathogenesis of and possible treatments for glioblastoma multiforme. Cancer Reports. 2019 Dec;2(6):e1193.
17. Khan N, Halcrow PW, Lakpa KL, Afghah Z, Miller NM, Dowdy SF, et al. Two‐pore channels regulate Tat endolysosome escape and Tat‐mediated HIV‐1 LTR transactivation. The FASEB Journal. 2020 Mar;34(3):4147-62.
18. Khan N, Lakpa KL, Halcrow PW, Afghah Z, Miller NM, Geiger JD, et al . BK channels regulate extracellular Tat-mediated HIV-1 LTR transactivation. Scientific Reports. 2019 Aug 22;9(1):1-4.
19. Afghah Z, Chen X, Geiger JD. Role of endolysosomes and inter-organellar signaling in brain disease. Neurobiology of Disease. 2020 Feb 1;134:104670.
20. Khan N, Haughey NJ, Nath A, Geiger JD. Involvement of organelles and inter-organellar signaling in the pathogenesis of HIV-1 associated neurocognitive disorder and Alzheimer’s disease. Brain Research. 2019 Nov 1;1722:146389.
21. Munz C. Antigen processing for MHC class II presentation via autophagy. Frontiers Inmmunology. 2012 Feb 2;3:9.
22. Bright NA, Davis LJ, Luzio JP. Endolysosomes are the principal intracellular sites of acid hydrolase activity. Current Biology. 2016 Sep 12;26(17):2233-45.
23. Bright NA, Gratian MJ, Luzio JP. Endocytic delivery to lysosomes mediated by concurrent fusion and kissing events in living cells. Current Biology. 2005 Feb 22;15(4):360-5.
24. Lakpa KL, Khan N, Afghah Z, Chen X, Geiger JD. Lysosomal stress response (LSR): Physiological importance and pathological relevance. Journal of Neuroimmune Pharmacology. 2021 Mar 22:1-9.
25. Truschel ST, Clayton DR, Beckel JM, Yabes JG, Yao Y, Wolf-Johnston A, et al. Age-related endolysosome dysfunction in the rat urothelium. PLoS One. 2018 Jun 8;13(6):e0198817.
26. Hui L, Chen X, Haughey NJ, Geiger JD. Role of endolysosomes in HIV-1 Tat-induced neurotoxicity. ASN neuro. 2012 May 16;4(4):AN20120017.
27. Staring J, Raaben M, Brummelkamp TR. Viral escape from endosomes and host detection at a glance. Journal of Cell Science. 2018 Aug 1;131(15):jcs216259.
28. Takano T, Wakayama Y, Doki T. Endocytic pathway of feline coronavirus for cell entry: differences in serotype-dependent viral entry pathway. Pathogens. 2019 Dec;8(4):300.
29. White JM, Whittaker GR. Fusion of enveloped viruses in endosomes. Traffic. 2016 Jun;17(6):593-614.
30. Zhou N, Pan T, Zhang J, Li Q, Zhang X, Bai C, et al. Glycopeptide antibiotics potently inhibit cathepsin l in the late endosome/lysosome and block the entry of ebola virus, middle east respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus (SARS-CoV). Journal of Biological Chemistry. 2016 Apr 22;291(17):9218-32.
31. Smith AE, Helenius A. How viruses enter animal cells. Science. 2004 Apr 9;304(5668):237-42.
32. Prentice E, Jerome WG, Yoshimori T, Mizushima N, Denison MR. Coronavirus replication complex formation utilizes components of cellular autophagy. Journal of Biological Chemistry. 2004 Mar 12;279(11):10136-41.
33. Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clinical Rheumatology. 2020 Jul;39:2085-94.
34. Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine & Growth Factor Reviews. 2020 Jun 1;53:66-70.
35. Chau VQ, Oliveros E, Mahmood K, Singhvi A, Lala A, Moss N, et al. The imperfect cytokine storm: severe COVID-19 with ARDS in a patient on durable LVAD support. Case Reports. 2020 Jul 15;2(9):1315-20.
36. Zhao M. Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies. International Journal of Antimicrobial Agents. 2020 Jun;55(6):105982.
37. Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodríguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine & Growth Factor Reviews. 2020 Aug 1;54:62-75.
38. Hu B, Huang S, Yin L. The cytokine storm and COVID-19. Journal of Medical Virology. 2021 Jan;93(1):250-6.
39. Yang L, Xie X, Tu Z, Fu J, Xu D, Zhou Y. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduction and Targeted Therapy. 2021 Jul 7;6(1):1-20.
40. Hojyo S, Uchida M, Tanaka K, Hasebe R, Tanaka Y, Murakami M, et al. How COVID-19 induces cytokine storm with high mortality. Inflammation And Regeneration. 2020 Dec;40(1):1-7.
41. Schloer S, Brunotte L, Goretzko J, Mecate-Zambrano A, Korthals N, Gerke V, et al. Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerging Microbes & Infections. 2020 Jan 1;9(1):2245-55.
42. Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, et al. SARS-CoV-2 variants, spike mutations and immune escape. Nature Reviews Microbiology. 2021 Jul;19(7):409-24.
43. Wang Z, Zhou M, Fu Z, Zhao L. The Pathogenic Features of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Possible Mechanisms for Immune Evasion? Frontiers in Immunology. 2021:2816.
44. Antony P, Vijayan R. Role of SARS-CoV-2 and ACE2 variations in COVID-19. Biomedical Journal. 2021 Apr 21.
45. Guo J, Huang Z, Lin L, Lv J. Coronavirus disease 2019 (COVID‐19) and cardiovascular disease: a viewpoint on the potential influence of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection. Journal of the American Heart Association. 2020 Apr 9;9(7):e016219.
46. Roshanravan N, Ghaffari S, Hedayati M. Angiotensin converting enzyme-2 as therapeutic target in COVID-19. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020 Jul 1;14(4):637-9.
47. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020 May 14;181(4):905-13.
48. Xia S, Lan Q, Pu J, Wang C, Liu Z, Xu W, et al. Potent MERS-CoV fusion inhibitory peptides identified from HR2 domain in spike protein of bat coronavirus HKU4. Viruses. 2019 Jan;11(1):56.
49. Xia S, Liu M, Wang C, Xu W, Lan Q, Feng S, et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Research. 2020 Apr;30(4):343-55.
50. Xia S, Yan L, Xu W, Agrawal AS, Algaissi A, Tseng CT, et al. A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike. Science Advances. 2019 Apr 1;5(4):eaav4580.
51. Coleman CM, Sisk JM, Mingo RM, Nelson EA, White JM, Frieman MB. Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus fusion. Journal of Virology. 2016 Sep 12;90(19):8924-33.
52. Hoffmann M, Kleine-Weber H, Pöhlmann S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Molecular Cell. 2020 May 21;78(4):779-84.
53. Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proceedings of the National Academy of Sciences. 2014 Oct 21;111(42):15214-9.
54. Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, Li F. Cell entry mechanisms of SARS-CoV-2. Proceedings of the National Academy of Sciences. 2020 May 26;117(21):11727-34.
55. Bosch BJ, Bartelink W, Rottier PJ. Cathepsin L functionally cleaves the severe acute respiratory syndrome coronavirus class I fusion protein upstream of rather than adjacent to the fusion peptide. Journal of Virology. 2008 Sep 1;82(17):8887-90.
56. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Research. 2020 Apr 1;176:104742.
57. Padmanabhan P, Desikan R, Dixit NM. Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection. PLoS Computational Biology. 2020 Dec 8;16(12):e1008461.
58. Padmanabhan P, Desikan R, Dixit NM. Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection. PLoS Computational Biology. 2020 Dec 8;16(12):e1008461.
59. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-80.
60. Glebov OO. Understanding SARS‐CoV‐2 endocytosis for COVID‐19 drug repurposing. The FEBS Journal. 2020 Sep;287(17):3664-71.
61. Ou T, Mou H, Zhang L, Ojha A, Choe H, Farzan M. Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2. PLoS Pathogens. 2021 Jan 19;17(1):e1009212.
62. Inoue Y, Tanaka N, Tanaka Y, Inoue S, Morita K, Zhuang M, et al. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. Journal of Virology. 2007 Aug 15;81(16):8722-9.
63. Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, et al. SARS coronavirus entry into host cells through a novel clathrin-and caveolae-independent endocytic pathway. Cell Research. 2008 Feb;18(2):290-301.
64. Burkard C, Verheije MH, Haagmans BL, van Kuppeveld FJ, Rottier PJ, Bosch BJ, et al. ATP1A1-mediated Src signaling inhibits coronavirus entry into host cells. Journal of Virology. 2015 Feb 4;89(8):4434-48.
65. Ko M, Chang SY, Byun SY, Ianevski A, Choi I, d’Alexandry AL, et al. Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for COVID-19. BioRxiv. 2020 Jan 1.
66. Ramsey ML, Nuttall J, Hart PA. A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of Camostat Treatment in Chronic Pancreatitis (TACTIC). Trials. 2019 Dec;20(1):1-7.
67. Baron SA, Devaux C, Colson P, Raoult D, Rolain JM. Teicoplanin: an alternative drug for the treatment of COVID-19?. International Journal of Antimicrobial Agents. 2020 Apr 1;55(4):105944.
68. Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature. 2020 Oct;586(7827):113-9.
69. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020 Mar;30(3):269-71..
70. Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018 Aug 3;14(8):1435-55.
71. Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020 Jul 1;56(1):105949.
72. Andreani J, Le Bideau M, Duflot I, Jardot P, Rolland C, Boxberger M, et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microbial Pathogenesis. 2020 Aug 1;145:104228.
73. Kazi MS, Saurabh K, Rishi P, Rishi E. Delayed onset chloroquine retinopathy presenting 10 years after long-term usage of chloroquine. Middle East African Journal of Ophthalmology. 2013 Jan;20(1):89.
74. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology. 2020 Mar;16(3):155-66.
75. Offerhaus JA, Wilde AA, Remme CA. Prophylactic (hydroxy) chloroquine in COVID-19: Potential relevance for cardiac arrhythmia risk. Heart Rhythm. 2020 Sep 1;17(9):1480-6.
76. Belizaire R, Unanue ER. Targeting proteins to distinct subcellular compartments reveals unique requirements for MHC class I and II presentation. Proceedings of the National Academy of Sciences. 2009 Oct 13;106(41):17463-8.
77. Kužnik A, Benčina M, Švajger U, Jeras M, Rozman B, Jerala R. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. The Journal of Immunology. 2011 Apr 15;186(8):4794-804.
78. Mary A, Hénaut L, Schmit JL, Lanoix JP, Brazier M. Therapeutic Options for Coronavirus Disease 2019 (COVID-19)-Modulation of Type I Interferon Response as a Promising Strategy? Frontiers in Public Health. 2020 May 15;8:185.
79. Yang A, Yang C, Yang B. Use of hydroxychloroquine and interferon alpha-2b for the prophylaxis of COVID-19. Medical Hypotheses. 2020 Nov 1;144:109802.
80. Schmeisser H, Bekisz J, Zoon KC. New function of type I IFN: induction of autophagy. Journal of Interferon & Cytokine Research. 2014 Feb 1;34(2):71-8.
81. Lee JS, Shin EC. The type I interferon response in COVID-19: implications for treatment. Nature Reviews Immunology. 2020 Oct;20(10):585-6.
82. Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nature communications. 2020 Mar 27;11(1):1-2.83.
83. Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, Klugbauer N, et al. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science. 2015 Feb 27;347(6225):995-8.
84. Kang YL, Chou YY, Rothlauf PW, Liu Z, Piccinotti S, Soh TK, et al, Whelan SP. Inhibition of PIKfyve kinase prevents infection by EBOV and SARS-CoV-2. BioRxiv. 2020 Jan 1.
85. Kirsch SA, Kugemann A, Carpaneto A, Böckmann RA, Dietrich P. Phosphatidylinositol-3, 5-bisphosphate lipid-binding-induced activation of the human two-pore channel 2. Cellular and Molecular Life Sciences. 2018 Oct;75(20):3803-15.
86. Ganley IG, Pfeffer SR. Cholesterol accumulation sequesters Rab9 and disrupts late endosome function in NPC1-deficient cells. Journal of Biological Chemistry. 2006 Jun 30;281(26):17890-9.
87. Höglinger D, Burgoyne T, Sanchez-Heras E, Hartwig P, Colaco A, Newton J, et al. NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress. Nature Communications. 2019 Sep 19;10(1):1-4.
88. Ballout RA, Sviridov D, Bukrinsky MI, Remaley AT. The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications. The FASEB Journal. 2020 Jun;34(6):7253-64.
89. Mingo RM, Simmons JA, Shoemaker CJ, Nelson EA, Schornberg KL, D'souza RS, et al. Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to NPC1+ endolysosomes is a rate-defining step. Journal of Virology. 2015 Mar 1;89(5):2931-43.
90. Lu F, Liang Q, Abi-Mosleh L, Das A, De Brabander JK, Goldstein JL, et al. Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection. Elife. 2015 Dec 8;4:e12177.
91. Wichit S, Hamel R, Bernard E, Talignani L, Diop F, Ferraris P, et al. Imipramine inhibits chikungunya virus replication in human skin fibroblasts through interference with intracellular cholesterol trafficking. Scientific Reports. 2017 Jun 9;7(1):1-2.
92. Kim DE, Min JS, Jang MS, Lee JY, Shin YS, Park CM, et al. Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus OC43 infection of MRC-5 human lung cells. Biomolecules. 2019 Nov;9(11):696.
93. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Bioscience Trends. 2020.
94. Lin CW, Tsai FJ, Wan L, Lai CC, Lin KH, Hsieh TH, et al. Binding interaction of SARS coronavirus 3CLpro protease with vacuolar-H+ ATPase G1 subunit. FEBS Letters. 2005 Nov 7;579(27):6089-94.
95. Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery. 2020 Mar;19(3):149-50.
96. Jomah S, Asdaq SM, Al-Yamani MJ. Clinical efficacy of antivirals against novel coronavirus (COVID-19): A review. Journal of Infection and Public Health. 2020 Aug 3.
97. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020 May 16;395(10236):1569-78.
98. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. 2020 Jun 1;178:104787.
99. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. ICON (Ivermectin in COvid Nineteen) study: Use of ivermectin is associated with lower mortality in hospitalized patients with COVID-19. Available at SSRN 3631261. 2020 Jun 16.
100. Pang X, Cui Y, Zhu Y. Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication. Acta Pharmacologica Sinica. 2020 Sep;41(9):1255-7.
101. Wösten‐van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin‐(1–7) or an angiotensin II receptor antagonist. The Journal of Pathology. 2011 Dec;225(4):618-27. Wösten‐van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin‐(1–7) or an angiotensin II receptor antagonist. The Journal of Pathology. 2011 Dec;225(4):618-27.
102. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020 May 26;323(20):2052-9.
103. Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Research. 2020 Jun 1;178:104791.
104. Prokunina-Olsson L, Alphonse N, Dickenson RE, Durbin JE, Glenn JS, Hartmann R, et al. COVID-19 and emerging viral infections: The case for interferon lambda. Journal of Experimental Medicine. 2020 May 4;217(5).
105. Zhou Q, Chen V, Shannon CP, Wei XS, Xiang X, Wang X, et al. Interferon-α2b Treatment for COVID-19. Frontiers in Immunology. 2020 May 15;11:1061.
106. Al-Rasheed NM, Fadda L, Attia HA, Sharaf IA, Mohamed AM, Al-Rasheed NM. Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats. Acta Pharmaceutica. 2017 Mar 31;67(1):125-35.
107. Qin W, Lu W, Li H, Yuan X, Li B, Zhang Q, et al. Melatonin inhibits IL1β-induced MMP9 expression and activity in human umbilical vein endothelial cells by suppressing NF-κB activation. The Journal of Endocrinology. 2012 May 22;214(2):145-53.
108. Thota C, Farmer T, Garfield RE, Menon R, Al-Hendy A. Vitamin D elicits anti-inflammatory response, inhibits contractile-associated proteins, and modulates Toll-like receptors in human myometrial cells. Reproductive Sciences. 2013 Apr;20(4):463-75.
109. Merzon E, Tworowski D, Gorohovski A, Vinker S, Golan Cohen A, Green I, et al. Low plasma 25 (OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study. The FEBS Journal. 2020 Sep;287(17):3693-702.
110. Mok CK, Ng YL, Ahidjo BA, Lee RC, Loe MW, Liu J, et al. Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis. BioRxiv. 2020 Jan 1.
111. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CS, et al. Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: a randomized clinical trial. JAMA. 2021 Mar 16;325(11):1053-60.
112. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora VM, Solway J. Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results. JAMA Network Open. 2021 Mar 1;4(3):e214117.
113. Giménez VM, Inserra F, Tajer CD, Mariani J, Ferder L, Reiter RJ, et al. Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment. Life Sciences. 2020 Aug 1;254:117808.
114. Choi SI, Kim KS, Oh JY, Jin JY, Lee GH, Kim EK. Melatonin induces autophagy via an mTOR‐dependent pathway and enhances clearance of mutant‐TGFBIp. Journal of Pineal Research. 2013 May;54(4):361-72.
115. Hu W, Zhang L, Li MX, Shen J, Liu XD, Xiao ZG, et al. Vitamin D3 activates the autolysosomal degradation function against Helicobacter pylori through the PDIA3 receptor in gastric epithelial cells. Autophagy. 2019 Apr 3;15(4):707-25.
116. Fredeking T, Zavala-Castro J, González-Martínez P, Moguel-Rodríguez W, Sanchez E, Foster M, et al. Dengue patients treated with doxycycline showed lower mortality associated to a reduction in IL-6 and TNF levels. Recent Patents on anti-Infective Drug Discovery. 2015 Apr 1;10(1):51-8.
117. Di Caprio R, Lembo S, Di Costanzo L, Balato A, Monfrecola G. Anti-inflammatory properties of low and high doxycycline doses: an in vitro study. Mediators of Inflammation. 2015 Oct;2015.
118. Mahmud R, Rahman MM, Alam I, Ahmed KG, Kabir AH, Sayeed SJ, et al. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. Journal of International Medical Research. 2021 May;49(5):03000605211013550.
119. Lee N, Chan KA, Hui DS, Ng EK, Wu A, Chiu RW, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. Journal of Clinical Virology. 2004 Dec 1;31(4):304-9.
120. Tomazini BM, Maia IS, Bueno FR, Silva MV, Baldassare FP, Costa EL, et al. COVID-19-associated ARDS treated with DEXamethasone (CoDEX): study design and rationale for a randomized trial. Revista Brasileira de Terapia Intensiva. 2020 Oct 12;32:354-62.
121. Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv. Preprint. 2020 Jun;10(2020.06):22-0137273.
122. Mikulska M, Nicolini L, Signori A, Di Biagio A, Cepulcri C, Russo C. Tocilizumab and steroid treatment in patients with severe COVID-19 pneumonia. medRxiv 2020: 2020.
123. Costeira R, Lee KA, Murray B, Christiansen C, Castillo-Fernandez J, Ni Lochlainn M, et al. Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study. PloS One. 2021 Sep 10;16(9):e0257051.
124. Khan F, Fabbri L, Stewart I, Smyth A, Robinson K, Jenkins G. A systematic review of Anakinra, Tocilizumab, Sarilumab and Siltuximab for coronavirus-related infections. medRxiv. 2020 Jan 1.
125. Pacha O, Sallman MA, Evans SE. COVID-19: a case for inhibiting IL-17?. Nature Reviews Immunology. 2020 Jun;20(6):345-6.
126. Luo W, Li YX, Jiang LJ, Chen Q, Wang T, Ye DW. Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19. Trends in Pharmacological Sciences. 2020 Aug 1;41(8):531-43.
127. Salesi M, Shojaie B, Farajzadegan Z, Salesi N, Mohammadi E. TNF-α Blockers Showed Prophylactic Effects in Preventing COVID-19 in Patients with Rheumatoid Arthritis and Seronegative Spondyloarthropathies: A Case–Control Study. Rheumatology and Therapy. 2021 Sep;8(3):1355-70.
128. Tobinick E. TNF-α inhibition for potential therapeutic modulation of SARS coronavirus infection. Current Medical Research and Opinion. 2004 Jan 1;20(1):39-40.
129. Rosas IO, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. New England Journal of Medicine. 2021 Apr 22;384(16):1503-16.
130. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. Jama. 2020 Aug 25;324(8):782-93.
131. Chen CY, Chen WC, Hsu CK, Chao CM, Lai CC. Clinical efficacy and safety of Janus kinase inhibitors for COVID-19: A systematic review and meta-analysis of randomized controlled trials. International Immunopharmacology. 2021 Oct 1;99:108027.
132. DiNicolantonio JJ, McCarty M, Barroso-Aranda J. Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections. Open Heart. 2021 Mar 1;8(1):e001568.
133. Gassen NC, Papies J, Bajaj T, Dethloff F, Emanuel J, Weckmann K, et al. Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics. BioRxiv. 2020 Jan 1.
134. Huang S, Liu YE, Zhang Y, Zhang R, Zhu C, Fan L, et al. Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner. Signal Transduction and Targeted Therapy. 2020 Nov 13;5(1):1-3.
135. Bradshaw PC, Seeds WA, Miller AC, Mahajan VR, Curtis WM. COVID-19: proposing a ketone-based metabolic therapy as a treatment to blunt the cytokine storm. Oxidative Medicine and Cellular Longevity. 2020 Sep 9;2020.
136. Alzaabi MM, Hamdy R, Ashmawy NS, Hamoda AM, Alkhayat F, Khademi NN, et al. Flavonoids are promising safe therapy against COVID-19. Phytochemistry Reviews. 2021 May 22:1-22.
137. Liesenborghs L, Spriet I, Jochmans D, Belmans A, Gyselinck I, Teuwen LA, et al. Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial. EBioMedicine. 2021 Apr 1;66:103288.
138. Chatterjee B, Thakur SS. ACE2 as a potential therapeutic target for pandemic COVID-19. RSC Advances. 2020;10(65):39808-13.
139. Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux C, et al. Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial. The Lancet Respiratory Medicine. 2021 May 1;9(5):498-510.
140. Wang Z, Pan H, Jiang B. Type I IFN deficiency: an immunological characteristic of severe COVID-19 patients. Signal Transduction and Targeted Therapy. 2020 Sep 14;5(1):1-2.
141. Lee JS, Shin EC. The type I interferon response in COVID-19: implications for treatment. Nature Reviews Immunology. 2020 Oct;20(10):585-6.
142. Yates PA, Newman SA, Oshry LJ, Glassman RH, Leone AM, Reichel E. Doxycycline treatment of high-risk COVID-19-positive patients with comorbid pulmonary disease. Therapeutic Advances in Respiratory Disease. 2020 Sep;14:1753466620951053.
143. Resende GG, da Cruz Lage R, Lobe SQ, Medeiros AF, e Silva AD, de Sa AT, et al. Blockade of Interleukin Seventeen (IL–17A) with Secukinumab in Hospitalized COVID–19 patients–the BISHOP study. medRxiv. 2021 Jan 1.
144. Guimarães PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, et al. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. New England Journal of Medicine. 2021 Jun 16.