Small molecules targeting endolysosomal acidification and signaling in sepsis and severe SARS-CoV-2 infection/COVID-19

Abstract

Sepsis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and its severe form coronavirus disease 2019 (COVID-19), represent the major medical challenges of the modern era. Therapeutic options are limited, mostly symptomatic, partially relying on antibodies and corticosteroids and, in the case of SARS-CoV-2 infection, supplemented by the antiviral drug remdesivir, and more recently by molnupiravir, nirmatrelvir/ritonavir, and the Janus kinase (JAK) inhibitors tofacitinib and baricitinib. Sepsis and severe SARS-CoV-2 infection/COVID-19 share many features at the level of pathophysiology and pro-inflammatory mediators, thus enabling a common disease management strategy. New ideas in successfully targeting the prognostic severity and mortality marker pentraxin 3 (PTX3) in sepsis and severe SARS-CoV-2 infection/COVID-19; the complement (C3/C3a/C3aR and C5/C5a/C5aR axis); tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 expression; IL-6-triggered expression of C5aR receptor in vascular endothelial cells; and release of anti-inflammatory IL-10 are still missing. Small molecules with lysosomotropic characteristics such as the approved drugs amitriptyline, desloratadine, fluvoxamine, azelastine, and ambroxol have demonstrated their clinical benefits in rodent models of sepsis or clinical trials in COVID-19; however, their exact mode of action remains to be fully elucidated. Addressing disease-relevant targets such as viral infection of host cells, shedding of toll-like receptors (TLRs), expression of pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, PTX3, and the complement receptor C5aR, highlight the advantages of this multi-target approach in comparison to current standards. Rational drug repurposing of approved drugs or screening for active compounds with virtually exclusively lysosomotropic pharmacologic effects is a major opportunity to improve prophylaxis and treatment of sepsis and/or SARS-CoV-2 infection, and its severe form COVID-19.

Keywords

Sepsis / COVID-19 / small molecules / lysosomotropism / drug repurposing / antibodies / lysosome / metabolites

References

[1] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315: 801-10.

[2] Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016; 2: 16045.

[3] Ma L, Sahu SK, Cano M, Kuppuswamy V, Bajwa J, McPhatter J, et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol. 2021; 6: eabh2259.

[4] Leisman DE, Ronner L, Pinotti R, Taylor MD, Sinha P, Calfee CS, et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med. 2020; 8: 1233-44.

[5] Bermejo-Martin JF, González-Rivera M, Almansa R, Micheloud D, Tedim AP, Domínguez-Gil M, et al. Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19. Crit Care. 2020; 24: 691.

[6] Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020; 71: 762-8.

[7] Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020; 20: 363-74.

[8] Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, et al. Complement activation and endothelial perturbation parallel COVID-19 severity and activity. J Autoimmun. 2021; 116: 102560.

[9] Brunetta E, Folci M, Bottazzi B, De Santis M, Gritti G, Protti A, et al. Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19. Nat Immunol. 2021; 22: 19-24.

[10] Del Turco S, Vianello A, Ragusa R, Caselli C, Basta G . COVID-19 and cardiovascular consequences: is the endothelial dysfunction the hardest challenge? Thromb Res. 2020; 196: 143-51.

[11] Lafon E, Diem G, Witting C, Zaderer V, Bellmann-Weiler RM, Reindl M, et al. Potent SARS-CoV-2-specific T cell immunity and low anaphylatoxin levels correlate with mild disease progression in COVID-19 patients. Front Immunol. 2021; 12: 684014.

[12] Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020; 27: 992-1000.e3.

[13] Boussier J, Yatim N, Marchal A, Hadjadj J, Charbit B, El Sissy C, et al. Severe COVID-19 is associated with hyperactivation of the alternative complement pathway. J Allergy Clin Immunol. 2022; 149: 550-6.e2.

[14] Kurtovic L, Beeson JG. Complement factors in COVID-19 therapeutics and vaccines. Trends Immunol. 2021; 42: 94-103.

[15] Teimury A, Khameneh MT, Khaledi EM. Major coagulation disorders and parameters in COVID-19 patients. Eur J Med Res. 2022; 27: 25.

[16] Coronavirus disease 2019 (COVID-19) treatment guidelines [Internet]. Bethesda: National Institutes of Health; c2022 [cited 2021 Oct 26]. Available from: https://www.covid19treatmentguidelines.nih.gov/

[17] Karakike E, Giamarellos-Bourboulis EJ, Kyprianou M, Fleischmann-Struzek C, Pletz MW, Netea MG, et al. Coronavirus disease 2019 as cause of viral sepsis: a systematic review and meta-analysis. Crit Care Med. 2021; 49: 2042-57.

[18] Hu Y, Xie GH, Chen QX, Fang XM. Small molecules in treatment of sepsis. Curr Drug Targets. 2011; 12: 256-62.

[19] Chung HY, Kollmey AS, Schrepper A, Kohl M, Bläss MF, Stehr SN, et al. Adjustment of dysregulated ceramide metabolism in a murine model of sepsis-induced cardiac dysfunction. Int J Mol Sci. 2017; 18: 839.

[20] Reis G, dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, 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: e42-51.

[21] Hoertel N, Sánchez-Rico M, Gulbins E, Kornhuber J, Carpinteiro A, Lenze EJ, et al. Association between FIASMAs and reduced risk of intubation or death in individuals hospitalized for severe COVID-19: an observational multicenter study. Clin Pharmacol Ther. 2021; 110: 1498-511.

[22] Blaess M, Bibak N, Claus RA, Kohl M, Bonaterra GA, Kinscherf R, et al. NB 06: from a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of lysosomes in signaling apoptosis and LPS-induced inflammation. Eur J Med Chem. 2018; 153: 73-104.

[23] Sakata A, Ochiai T, Shimeno H, Hikishima S, Yokomatsu T, Shibuya S, et al. Acid sphingomyelinase inhibition suppresses lipopolysaccharide-mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium-induced colitis in mice. Immunology. 2007; 122: 54-64.

[24] Lockwood TD. The lysosome among targets of metformin: new anti-inflammatory uses for an old drug? Expert Opin Ther Targets. 2010; 14: 467-78.

[25] Norinder U, Tuck A, Norgren K, Munic Kos V. Existing highly accumulating lysosomotropic drugs with potential for repurposing to target COVID-19. Biomed Pharmacother. 2020; 130: 110582.

[26] Chung HY, Hupe DC, Otto GP, Sprenger M, Bunck AC, Dorer MJ, et al. Acid sphingomyelinase promotes endothelial stress response in systemic inflammation and sepsis. Mol Med. 2016; 22: 412-23.

[27] Liszewski KM, Kolev M, Bertram P, Yamamoto H, Leung MK, Atkinson JP, et al. Cleavage of intracellular C3 into C3a and C3b by cathepsin L is required for human TH1 induction. Immunobiology. 2012; 217: 1150.

[28] Ghosh S, Dellibovi-Ragheb TA, Kerviel A, Pak E, Qiu Q, Fisher M, et al. β-coronaviruses use lysosomes for egress instead of the biosynthetic secretory pathway. Cell. 2020; 183: 1520-35.e14.

[29] Kolter T, Sandhoff K. Lysosomal degradation of membrane lipids. FEBS Lett. 2010; 584: 1700-12.

[30] Plaze M, Attali D, Petit AC, Blatzer M, Simon-Loriere E, Vinckier F, et al. Repurposing chlorpromazine to treat COVID-19: the reCoVery study. Encephale. 2020; 46: 169-72.

[31] Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382: 727-33.

[32] Qiu Y, Zhao YB, Wang Q, Li JY, Zhou ZJ, Liao CH, et al. Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2. Microbes Infect. 2020; 22: 221-5.

[33] Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol. 2022; 23: 3-20.

[34] 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. Nat Commun. 2020; 11: 1620. Erratum in: Nat Commun. 2021;12:2144.

[35] 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; 181: 271-80.e8.

[36] Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020; 181: 281-92.e6. Erratum in: Cell. 2020;183:1735.

[37] Bayati A, Kumar R, Francis V, McPherson PS. SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. J Bio Chem. 2021; 296: 100306.

[38] Anguiano L, Riera M, Pascual J, Soler MJ. Circulating ACE2 in cardiovascular and kidney diseases. Curr Med Chem. 2017; 24: 3231-41.

[39] Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-7.

[40] Blaess M, Kaiser L, Sauer M, Csuk R, Deigner HP. COVID-19/SARS-CoV-2 infection: lysosomes and lysosomotropism implicate new treatment strategies and personal risks. Int J Mol Sci. 2020; 21: 4953.

[41] Blaess M, Kaiser L, Sommerfeld O, Rentschler S, Csuk R, Deigner HP. Rational drug repurposing: focus on lysosomotropism, targets in disease process, drug profile, and pulmonary tissue accumulation in SARS-CoV-2 infection/COVID-19. Front Pharmacol. 2020; 11: 584881.

[42] Olwal CO, Nganyewo NN, Tapela K, Djomkam Zune AL, Owoicho O, Bediako Y, et al. Parallels in sepsis and COVID-19 conditions: implications for managing severe COVID-19. Front Immunol. 2021; 12: 602848.

[43] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395: 497-506.

[44] Wilson JG, Simpson LJ, Ferreira AM, Rustagi A, Roque J, Asuni A, et al. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI Insight. 2020; 5: e140289.

[45] Dong X, Wang C, Liu X, Gao W, Bai X, Li Z. Lessons learned comparing immune system alterations of bacterial sepsis and SARS-CoV-2 sepsis. Front Immunol. 2020; 11: 598404.

[46] Carvelli J, Demaria O, Vély F, Batista L, Chouaki Benmansour N, Fares J, et al. Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis. Nature. 2020; 588: 146-50.

[47] Fjell CD, Thair S, Hsu JL, Walley KR, Russell JA, Boyd J. Cytokines and signaling molecules predict clinical outcomes in sepsis. PLoS One. 2013; 8: e79207.

[48] Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007; 11: R49.

[49] Razazi K, Boissier F, Surenaud M, Bedet A, Seemann A, Carteaux G, et al. A multiplex analysis of sepsis mediators during human septic shock: a preliminary study on myocardial depression and organ failures. Ann Intensive Care. 2019; 9: 64.

[50] Mera S, Tatulescu D, Cismaru C, Bondor C, Slavcovici A, Zanc V, et al. Multiplex cytokine profiling in patients with sepsis. APMIS. 2011; 119: 155-63.

[51] Tian R, Wang X, Pan T, Li R, Wang J, Liu Z, et al. Plasma PTX3, MCP1 and Ang2 are early biomarkers to evaluate the severity of sepsis and septic shock. Scand J Immunol. 2019; 90: e12823.

[52] Lvovschi V, Arnaud L, Parizot C, Freund Y, Juillien G, Ghillani-Dalbin P, et al. Cytokine profiles in sepsis have limited relevance for stratifying patients in the emergency department: a prospective observational study. PLoS One. 2011; 6: e28870.

[53] Matsumoto H, Ogura H, Shimizu K, Ikeda M, Hirose T, Matsuura H, et al. The clinical importance of a cytokine network in the acute phase of sepsis. Sci Rep. 2018; 8: 13995.

[54] Gomez HG, Gonzalez SM, Londoño JM, Hoyos NA, Niño CD, Leon AL, et al. Immunological characterization of compensatory anti-inflammatory response syndrome in patients with severe sepsis: a longitudinal study*. Crit Care Med. 2014; 42: 771-80.

[55] Mosevoll KA, Skrede S, Markussen DL, Fanebust HR, Flaatten HK, Aßmus J, et al. Inflammatory mediator profiles differ in sepsis patients with and without bacteremia. Front Immunol. 2018; 9: 691.

[56] Ren J, Zhao Y, Yuan Y, Han G, Li W, Huang Q, et al. Complement depletion deteriorates clinical outcomes of severe abdominal sepsis: a conspirator of infection and coagulopathy in crime? PLoS One. 2012; 7: e47095.

[57] Andaluz-Ojeda D, Iglesias V, Bobillo F, Almansa R, Rico L, Gandía F, et al. Early natural killer cell counts in blood predict mortality in severe sepsis. Crit Care. 2011; 15: R243.

[58] Furebring M, Håkansson LD, Venge P, Nilsson B, Sjölin J. Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis. Crit Care. 2002; 6: 363-70.

[59] Younger JG, Bracho DO, Chung-Esaki HM, Lee M, Rana GK, Sen A, et al. Complement activation in emergency department patients with severe sepsis. Acad Emerg Med. 2010; 17: 353-9.

[60] Mauri T, Bellani G, Patroniti N, Coppadoro A, Peri G, Cuccovillo I, et al. Persisting high levels of plasma pentraxin 3 over the first days after severe sepsis and septic shock onset are associated with mortality. Intensive Care Med. 2010; 36: 621-9.

[61] Muller B, Peri G, Doni A, Torri V, Landmann R, Bottazzi B, et al. Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med. 2001; 29: 1404-7.

[62] Caironi P, Masson S, Mauri T, Bottazzi B, Leone R, Magnoli M, et al. Pentraxin 3 in patients with severe sepsis or shock: the ALBIOS trial. Eur J Clin Invest. 2017; 47: 73-83.

[63] Zhao Y, Qin L, Zhang P, Li K, Liang L, Sun J, et al. Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. JCI Insight. 2020; 5: e139834.

[64] Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020; 584: 463-9.

[65] Kuśnierz-Cabala B, Maziarz B, Dumnicka P, Dembiński M, Kapusta M, Bociąga-Jasik M, et al. Diagnostic significance of serum galectin-3 in hospitalized patients with COVID-19-a preliminary study. Biomolecules. 2021; 11: 1136.

[66] Rafiee L, Hajhashemi V, Javanmard SH. Fluvoxamine inhibits some inflammatory genes expression in LPS/stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat. Iran J Basic Med Sci. 2016; 19: 977-84.

[67] Xia BT, Beckmann N, Winer LK, Pugh AM, Pritts TA, Nomellini V, et al. Amitriptyline reduces inflammation and mortality in a murine model of sepsis. Cell Physiol Biochem. 2019; 52: 565-79.

[68] Zhang SJ, Jiang JX, Ren QQ, Jia YL, Shen J, Shen HJ, et al. Ambroxol inhalation ameliorates LPS-induced airway inflammation and mucus secretion through the extracellular signal-regulated kinase 1/2 signaling pathway. Eur J Pharmacol. 2016; 775: 138-48.

[69] Lee YT, Gong M, Chau A, Wong WT, Bazoukis G, Wong SH, et al. Pentraxin-3 as a marker of sepsis severity and predictor of mortality outcomes: a systematic review and meta-analysis. J Infect. 2018; 76: 1-10.

[70] He X, Han B, Bai X, Zhang Y, Cypel M, Mura M, et al. PTX3 as a potential biomarker of acute lung injury: supporting evidence from animal experimentation. Intensive Care Med. 2010; 36: 356-64.

[71] Protti A, Meessen J, Bottazzi B, Garlanda C, Milani A, Bacci M, et al. Circulating pentraxin 3 in severe COVID-19 or other pulmonary sepsis. Eur J Clin Invest. 2021; 51: e13530.

[72] Kox M, Frenzel T, Schouten J, van de Veerdonk FL, Koenen HJPM, Pickkers P, et al. COVID-19 patients exhibit less pronounced immune suppression compared with bacterial septic shock patients. Crit Care. 2020; 24: 263.

[73] Remy KE, Mazer M, Striker DA, Ellebedy AH, Walton AH, Unsinger J, et al. Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections. JCI Insight. 2020; 5: e140329.

[74] Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010; 20: 34-50.

[75] Garred P, Tenner AJ, Mollnes TE. Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol Rev. 2021; 73: 792-827.

[76] Liszewski MK, Kolev M, Le Friec G, Leung M, Bertram PG, Fara AF, et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity. 2013; 39: 1143-57.

[77] Ward PA. The dark side of C5a in sepsis. Nat Rev Immunol. 2004; 4: 133-42.

[78] Barratt-Due A, Pischke SE, Nilsson PH, Espevik T, Mollnes TE. Dual inhibition of complement and toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets. J Leukoc Biol. 2017; 101: 193-204.

[79] Heeger PS, Kemper C. Novel roles of complement in T effector cell regulation. Immunobiology. 2012; 217: 216-24.

[80] Carroll MC. The complement system in regulation of adaptive immunity. Nat Immunol. 2004; 5: 981-6.

[81] Carroll MC. The complement system in B cell regulation. Mol Immunol. 2004; 41: 141-6.

[82] Chouaki Benmansour N, Carvelli J, Vivier E. Complement cascade in severe forms of COVID-19: recent advances in therapy. Eur J Immunol. 2021; 51: 1652-9.

[83] Bauer M, Weyland A, Marx G, Bloos F, Weber S, Weiler N, et al. Efficacy and safety of vilobelimab (IFX-1), a novel monoclonal anti-C5a antibody, in patients with early severe sepsis or septic shock-a randomized, placebo-controlled, double-blind, multicenter, phase IIa trial (SCIENS study). Crit Care Explor. 2021; 3: e0577.

[84] Sommerfeld O, Medyukhina A, Neugebauer S, Ghait M, Ulferts S, Lupp A, et al. Targeting complement C5a receptor 1 for the treatment of immunosuppression in sepsis. Mol Ther. 2021; 29: 338-46.

[85] Fairhead M, van der Walle CF. The heavy-light chain loop of human cathepsin-L modulates its activity and stability. Protein Pept Lett. 2008; 15: 47-53.

[86] Pillay CS, Elliott E, Dennison C. Endolysosomal proteolysis and its regulation. Biochem J. 2002; 363: 417-29.

[87] Hess C, Kemper C. Complement-mediated regulation of metabolism and basic cellular processes. Immunity. 2016; 45: 240-54.

[88] De Nardo D. Toll-like receptors: activation, signalling and transcriptional modulation. Cytokine. 2015; 74: 181-9.

[89] Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007; 7: 767-77.

[90] Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, et al. CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell. 2011; 147: 868-80.

[91] McGettrick AF, O’Neill LA. Localisation and trafficking of toll-like receptors: an important mode of regulation. Curr Opin Immunol. 2010; 22: 20-7.

[92] Qian Z, Dominguez SR, Holmes KV. Role of the spike glycoprotein of human middle east respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. PLoS One. 2013; 8: e76469.

[93] 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 . J Virol. 2015; 89: 2931-43.

[94] Dehrmann FM, Coetzer TH, Pike RN, Dennison C. Mature cathepsin L is substantially active in the ionic milieu of the extracellular medium. Arch Biochem Biophys. 1995; 324: 93-8.

[95] Millet JK, Whittaker GR. Host cell proteases: critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015; 202: 120-34.

[96] Gille L, Nohl H. The existence of a lysosomal redox chain and the role of ubiquinone. Arch Biochem Biophys. 2000; 375: 347-54.

[97] Nishi T, Forgac M. The vacuolar (H⁺)-ATPases - nature’s most versatile proton pumps . Nat Rev Mol Cell Biol. 2002; 3: 94-103.

[98] Weston S, Coleman CM, Haupt R, Logue J, Matthews K, Li Y, et al. Broad anti-coronavirus activity of food and drug administration-approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo . J Virol. 2020; 94: e01218-20.

[99] Gour-Salin BJ, Lachance P, Magny MC, Plouffe C, Ménard R, Storer AC. E64 [trans-epoxysuccinyl- L-leucylamido-(4-guanidino)butane] analogues as inhibitors of cysteine proteinases: investigation of S2 subsite interactions . Biochem J. 1994; 299: 389-92.

[100] Gorshkov K, Chen CZ, Bostwick R, Rasmussen L, Tran BN, Cheng YS, et al. The SARS-CoV-2 cytopathic effect is blocked by lysosome alkalizing small molecules. ACS Infect Dis. 2021; 7: 1389-408.

[101] Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H⁺-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells . J Biol Chem. 1991; 266: 17707-12.

[102] Ohkuma S, Poole B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci U S A. 1978; 75: 3327-31.

[103] Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021; 49: e1063-143.

[104] German national treatment guidance for hospitalized-COVID-19 patients. Chirurg. 2021; 92: 850. German.

[105] Murrell DF, Rudnicka L, Shivakumar S, Kassir M, Jafferany M, Galadari H, et al. Biologics and small molecules in the treatment of COVID-19. J Drugs Dermatol. 2020; 19: 673-5.

[106] Blüml S. Biologicals and small molecules for rheumatoid arthritis. Z Rheumatol. 2020; 79: 223-31. Erratum in: Z Rheumatol. 2020; 79:446. German.

[107] Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘cytokine storm’ in COVID-19. J Infect. 2020; 80: 607-13.

[108] Mansourabadi AH, Sadeghalvad M, Mohammadi-Motlagh HR, Rezaei N. The immune system as a target for therapy of SARS-CoV-2: a systematic review of the current immunotherapies for COVID-19. Life Sci. 2020; 258: 118185.

[109] Yang L, Liu S, Liu J, Zhang Z, Wan X, Huang B, et al. COVID-19: immunopathogenesis and immunotherapeutics. Signal Transduct Target Ther. 2020; 5: 128.

[110] Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial . JAMA. 2020; 324: 2292-300.

[111] Blaess M, Kaiser L, Sommerfeld O, Csuk R, Deigner HP. Drugs, metabolites, and lung accumulating small lysosomotropic molecules: multiple targeting impedes SARS-CoV-2 infection and progress to COVID-19. Int J Mol Sci. 2021; 22: 1797.

[112] Posch W, Vosper J, Noureen A, Zaderer V, Witting C, Bertacchi G, et al. C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2-infected primary human airway epithelia. J Allergy Clin Immunol. 2021; 147: 2083-97.e6.

[113] Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003; 9: 517-24.

[114] Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis: Crit Care Med. 2010; 38: 1685-94.

[115] Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. 2020; 64: e00399-20.

[116] Perrin-Cocon L, Aublin-Gex A, Sestito SE, Shirey KA, Patel MC, André P, et al. TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection. Sci Rep. 2017; 7: 40791.

[117] Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. TAK-242 selectively suppresses toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008; 584: 40-8.

[118] Wang H, Ward MF, Sama AE. Targeting HMGB1 in the treatment of sepsis. Expert Opin Ther Targets. 2014; 18: 257-68.

[119] Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, et al. Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med. 2021; 385: 1941-50.

[120] Cameroni E, Bowen JE, Rosen LE, Saliba C, Zepeda SK, Culap K, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 omicron antigenic shift. Nature. 2022; 602: 664-70.

[121] Harrison C. Focus shifts to antibody cocktails for COVID-19 cytokine storm. Nat Biotechnol. 2020; 38: 905-8.

[122] Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020; 16: 155-66.

[123] Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro . Cell Discov. 2020; 6: 16.

[124] Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020; 75: 1667-70.

[125] Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . Clin Infect Dis. 2020; 71: 732-9.

[126] Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial . JAMA Netw Open. 2020; 3: e208857.

[127] De Duve C, De Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F. Commentary. Lysosomotropic agents. Biochem Pharmacol. 1974; 23: 2495-531.

[128] Nadanaciva S, Lu S, Gebhard DF, Jessen BA, Pennie WD, Will Y. A high content screening assay for identifying lysosomotropic compounds. Toxicology In Vitro. 2011; 25: 715-23.

[129] Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, et al. Identification of new functional inhibitors of acid sphingomyelinase using a structure−property−activity relation model. J Med Chem. 2008; 51: 219-37.

[130] Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, et al. Identification of novel functional inhibitors of acid sphingomyelinase. PLoS One. 2011; 6: e23852.

[131] Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacol. 2015; 23: 231-69.

[132] Carpinteiro A, Gripp B, Hoffmann M, Pöhlmann S, Hoertel N, Edwards MJ, et al. Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells. J Biol Chem. 2021; 296: 100701.

[133] Villoutreix BO, Krishnamoorthy R, Tamouza R, Leboyer M, Beaune P. Chemoinformatic analysis of psychotropic and antihistaminic drugs in the light of experimental anti-SARS-CoV-2 activities. Adv Appl Bioinform Chem. 2021; 14: 71-85.

[134] Klussmann JP, Lehmann C, Grosheva M, Sahin K, Nagy E, Szijártó V, et al. COVID-19: azelastine nasal spray reduces virus-load in nasal swabs (CARVIN). Early intervention with azelastine nasal sprays reduces viral load in SARS-CoV-2 infected patients. First report on a double-blind placebo-controlled Phase II clinical trial. Research Square [Preprint]. c2021 [cited 2021 Oct 26]. Available from: https://www.researchsquare.com/article/rs-864566/v1

[135] Johnson RD, Lewis RJ, Angier MK. The distribution of fluoxetine in human fluids and tissues. J Anal Toxicol. 2007; 31: 409-14.

[136] Brockbals L, Staeheli SN, Gascho D, Ebert LC, Kraemer T, Steuer AE. Time- and site-dependent postmortem redistribution of antidepressants and neuroleptics in blood and alternative matrices. J Anal Toxicol. 2021; 45: 356-67.

[137] Song N, Fang Y, Sun X, Jiang Q, Song C, Chen M, et al. Salmeterol, agonist of β2-aderenergic receptor, prevents systemic inflammation via inhibiting NLRP3 inflammasome. Biochem Pharmacol. 2018; 150: 245-55.

[138] Gill SK, Marriott HM, Suvarna SK, Peachell PT. Evaluation of the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages. Eur J Pharmacol. 2016; 793: 49-55.

[139] Thomas RL Jr, Matsko CM, Lotze MT, Amoscato AA . Mass spectrometric identification of increased C16 ceramide levels during apoptosis. J Biol Chem. 1999; 274: 30580-8.

[140] Jaffrézou JP, Levade T, Bettaïeb A, Andrieu N, Bezombes C, Maestre N, et al. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J. 1996; 15: 2417-24.

[141] Okino N, He X, Gatt S, Sandhoff K, Ito M, Schuchman EH. The reverse activity of human acid ceramidase. J Biol Chem. 2003; 278: 29948-53.

[142] Tang N, Ong WY, Zhang EM, Chen P, Yeo JF. Differential effects of ceramide species on exocytosis in rat PC12 cells. Exp Brain Res. 2007; 183: 241-7.

[143] Garner OB, Aguilar HC, Fulcher JA, Levroney EL, Harrison R, Wright L, et al. Endothelial galectin-1 binds to specific glycans on nipah virus fusion protein and inhibits maturation, mobility, and function to block syncytia formation. PLoS Pathog. 2010; 6: e1000993.

[144] Masters PS. The molecular biology of coronaviruses. Adv Virus Res. 2006; 66: 193-292.

[145] Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, et al. The ectodomain of toll-like receptor 9 is cleaved to generate a functional receptor. Nature. 2008; 456: 658-62.

[146] Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol. 2010; 10: 170-81.

[147] Oberholzer A, Oberholzer C, Moldawer LL. Interleukin-10: a complex role in the pathogenesis of sepsis syndromes and its potential as an anti-inflammatory drug. Crit Care Med. 2002; 30: S58-63.

[148] Aste-Amezaga M, Ma X, Sartori A, Trinchieri G. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J Immunol. 1998; 160: 5936-44.

[149] Sikka G, Miller KL, Steppan J, Pandey D, Jung SM, Fraser CD 3rd, et al. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age. Exp Gerontol. 2013; 48: 128-35.

[150] Oberholzer C, Oberholzer A, Bahjat FR, Minter RM, Tannahill CL, Abouhamze A, et al. Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis. Proc Natl Acad Sci U S A. 2001; 98: 11503-8.

[151] Chung HY, Witt CJ, Jbeily N, Hurtado-Oliveros J, Giszas B, Lupp A, et al. Acid sphingomyelinase inhibition prevents development of sepsis sequelae in the murine liver. Sci Rep. 2017; 7: 12348.

[152] He X, Han B, Liu M. Long pentraxin 3 in pulmonary infection and acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2007; 292: L1039-49.

[153] Carrizzo A, Lenzi P, Procaccini C, Damato A, Biagioni F, Ambrosio M, et al. Pentraxin 3 induces vascular endothelial dysfunction through a P-selectin/matrix metalloproteinase-1 pathway . Circulation. 2015; 131: 1495-505.

[154] Garlanda C, Bottazzi B, Magrini E, Inforzato A, Mantovani A. PTX3, a humoral pattern recognition molecule, in innate immunity, tissue repair, and cancer. Physiol Rev. 2018; 98: 623-39.

[155] Doni A, Garlanda C, Bottazzi B, Meri S, Garred P, Mantovani A. Interactions of the humoral pattern recognition molecule PTX3 with the complement system. Immunobiology. 2012; 217: 1122-8.

[156] Latini R, Maggioni AP, Peri G, Gonzini L, Lucci D, Mocarelli P, et al. Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction. Circulation. 2004; 110: 2349-54.

[157] Deigner HP, Claus R, Bonaterra GA, Gehrke C, Bibak N, Blaess M, et al. Ceramide induces aSMase expression: implications for oxLDL-induced apoptosis. FASEB J. 2001; 15: 807-14.

[158] Snezhkina AV, Kudryavtseva AV, Kardymon OL, Savvateeva MV, Melnikova NV, Krasnov GS, et al. ROS generation and antioxidant defense systems in normal and malignant cells. Oxid Med Cell Longev. 2019; 2019: 6175804.

[159] Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta. 2011; 1807: 726-34.

[160] Seo I, Jha BK, Lim JG, Suh SI, Suh MH, Baek WK. Identification of lysosomotropic compounds based on the distribution and size of lysosomes. Biochem Biophys Res Commun. 2014; 450: 189-94.

[161] Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014; 6: 263ra159.

[162] Chung HY, Witt CJ, Hurtado-Oliveros J, Wickel J, Gräler MH, Lupp A, et al. Acid sphingomyelinase inhibition stabilizes hepatic ceramide content and improves hepatic biotransformation capacity in a murine model of polymicrobial sepsis. Int J Mol Sci. 2018; 19: 3163.

[163] Roumestan C, Michel A, Bichon F, Portet K, Detoc M, Henriquet C, et al. Anti-inflammatory properties of desipramine and fluoxetine. Respir Res. 2007; 8: 35.

[164] Huang HC, Shieh CC, Yu WL, Cheng KC, Chen CC, Chang ST, et al. Comparing the protective effects of ciprofloxacin, moxifloxacin and levofloxacin in mice with lipopolysaccharide-induced acute lung injuries. Respirology. 2008; 13: 47-52.

[165] Repurposing of chlorpromazine in Covid-19 treatment (reCoVery) [Internet]. Bethesda: U. S. National Library of Medicine. c2020 [cited 2020 May 7]. Available from: https://clinicaltrials.gov/ct2/show/NCT04366739

[166] Sánchez-Rico M, Limosin F, Vernet R, Beeker N, Neuraz A, Blanco C, et al. Hydroxyzine use and mortality in patients hospitalized for COVID-19: a multicenter observational study. J Clin Med. 2021; 10: 5891.

[167] Ge S, Lu J, Hou Y, Lv Y, Wang C, He H. Azelastine inhibits viropexis of SARS-CoV-2 spike pseudovirus by binding to SARS-CoV-2 entry receptor ACE2. Virology. 2021; 560: 110-5.

[168] Reznikov LR, Norris MH, Vashisht R, Bluhm AP, Li D, Liao YSJ, et al. Identification of antiviral antihistamines for COVID-19 repurposing. Biochem Biophys Res Commun. 2021; 538: 173-9.

[169] Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C, Muehlbacher M, et al. Functional inhibitors of acid sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. Cell Physiol Biochem. 2010; 26: 9-20.

[170] Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, et al. Repurposing of clinically developed drugs for treatment of middle east respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014; 58: 4885-93.

[171] 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. Emerg Microbes Infect. 2020; 9: 2245-55.

[172] Brunsdon P, Saluja B, Sahajwalla C. Clinical pharmacology considerations for developing small-molecule treatments for COVID-19. J Clin Pharmacol. 2020; 60: 1147-54.

[173] Loratadine [Internet]. Auckland: Drugs.com; c2020 [cited 2021 Jan 26]. Available from: https://www.drugs.com/loratadine.html

[174] Ambroxol Hydrochloride [Internet]. Auckland: Drugs.com; c2020 [cited 2021 Jan 26]. Available from: https://www.drugs.com/ambroxol.html

[175] Riedemann NC, Guo RF, Neff TA, Laudes IJ, Keller KA, Sarma VJ, et al. Increased C5a receptor expression in sepsis. J Clin Invest. 2002; 110: 101-8.

[176] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014; 124: 188-95.

[177] Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395: 1033-4.

[178] Manchanda H, Seidel N, Blaess MF, Claus RA, Linde J, Slevogt H, et al. Differential biphasic transcriptional host response associated with coevolution of hemagglutinin quasispecies of influenza A virus. Front Microbiol. 2016; 7: 1167.

[179] Dahlke K, Wrann CD, Sommerfeld O, Soßdorf M, Recknagel P, Sachse S, et al. Distinct different contributions of the alternative and classical complement activation pathway for the innate host response during sepsis. J Immunol. 2011; 186: 3066-75.

[180] Coulthard LG, Woodruff TM. Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J Immunol. 2015; 194: 3542-8.

[181] Laudes IJ, Chu JC, Huber-Lang M, Guo RF, Riedemann NC, Sarma JV, et al. Expression and function of C5a receptor in mouse microvascular endothelial cells. J Immunol. 2002; 169: 5962-70.