The Potential Therapeutic Role of Proton Pump Inhibitors in COVID-19: Hypotheses Based on Existing EvidencesFunding: This study has not received any specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Although the major therapeutic uses of the proton pump inhibitors are in gastric-acid related diseases, evidences are suggestive of a pleiotropic nature of the compounds. We comment on the probable pathways and cellular machineries via which proton pump inhibitors could show beneficial therapeutic effects against SARS-CoV-2 based on the existing evidences. Proton pump inhibitors have shown antiviral potencies in various in vivo and in vitro studies. Some of the major possible ways through which they can act against SARS-CoV-2 are by exerting anti-inflammatory and anti-fibrotic effects, via vacuolar ATPase pumps leading to raised endolysosomal pH and by targeting endosomal complexes. The current pandemic has put forward a challenge to find treatment options. Although the potential roles of proton pump inhibitors against SARS-CoV-2 have been discussed in recent publications, the clinical evidences for their real-world effectiveness do not point towards a beneficial effect clearly yet. We suggest that although proton pump inhibitors should strongly be considered as potential therapeutic options for COVID-19, larger studies in the form of randomized controlled trials would be required to arrive at a definite conclusion.
Key wordspharmacology - molecular pharmacology - infectious diseases - gastrointestinal pharmacology - antiviral drugs
Received: 26 June 2020
Accepted: 01 August 2020
02 September 2020 (online)
© 2020. Thieme. All rights reserved.
© Georg Thieme Verlag KG
Stuttgart · New York
- 1 Kaur G, Kaur M, Silakari O. Benzimidazoles: an ideal privileged drug scaffold for the design of multitargeted anti-inflammatory ligands. Mini Rev Med Chem 2014; 14: 747-767
- 2 PubChem Database. Method of using (H+/K+) ATPase inhibitors as antiviral agents. 1996 https://pubchem.ncbi.nlm.nih.gov/patent/US5945425, accessed on July 29, 2020
- 3 Sasaki T, Nakayama K, Yasuda H. et al. A new strategy with proton pump inhibitors for the prevention of acute exacerbations in COPD. Ther Adv Respir Dis 2011; 5: 91-103
- 4 Becker JC, Grosser N, Waltke C. et al. Beyond gastric acid reduction: proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells. Biochem Biophys Res Commun 2006; 345: 1014-1021
- 5 LEGW Vanfleteren, Spruit MA, EFM Wouters, FME Franssen. Management of chronic obstructive pulmonary disease beyond the lungs. Lancet Respir Med 2016; 4: 911-924
- 6 Ohara T, Arakawa T. Lansoprazole decreases peripheral blood monocytes and intercellular adhesion molecule-1-positive mononuclear cells. Dig Dis Sci 1999; 44: 1710-1715
- 7 Kountouras J, Boura P, Lygidakis NJ. Omeprazole and regulation of cytokine profile in Helicobacter pylori-infected patients with duodenal ulcer disease. Hepatogastroenterology 2000; 47: 1301-1304
- 8 Ghebre YT, Raghu G. Idiopathic pulmonary fibrosis: Novel concepts of proton pump inhibitors as antifibrotic drugs. Am J Respir Crit Care Med 2016; 193: 1345-1352
- 9 Shi H, Han X, Jiang N. et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020; 20: 425-434
- 10 Zhang T, Sun LX, Feng RE. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019. 2020; 43: 496-502 Chinese DOI: 10.3760/cma.j.cn112147-20200311-00312.
- 11 Mo X, Jian W, Su Z. et al. Abnormal pulmonary function in COVID-19 patients at time of hospital discharge. Eur Respir J 2020; 55 (06) 2001217
- 12 Zhang H. A Randomized, Open-label Study to Evaluate the Efficacy and Safety of Pirfenidone in Patients With Severe and Critical Novel Coronavirus Infection. . https://clinicaltrials.gov/ct2/show/NCT04282902 accessed on July 29 2020
- 13 Chen M, Lu J, Wei W. et al. Effects of proton pump inhibitors on reversing multidrug resistance via downregulating V-ATPases/PI3K/Akt/mTOR/HIF-1α signaling pathway through TSC1/2 complex and Rheb in human gastric adenocarcinoma cells in vitro and in vivo. Onco Targets Ther 2018; 11: 6705-6722
- 14 De Milito A, Iessi E, Logozzi M. et al. Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 2007; 67 (11) 5408-5417
- 15 Pamarthy S, Kulshrestha A, Katara GK. et al. The curious case of vacuolar ATPase: regulation of signaling pathways. Mol Cancer 2018; 17 (01) 41 DOI: 10.1186/s12943-018-0811-3.
- 16 Udelnow A, Kreyes A, Ellinger S. et al. Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PLoS One 2011; 6 (05) e20143
- 17 Belouzard S, Millet JK, Licitra BN. et al. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 2012; 4: 1011-1033
- 18 Mazzon M, Marsh M. Targeting viral entry as a strategy for broad-spectrum antivirals F1000Res. 2019 8. F1000 Faculty Rev-1628. DOI: 10.12688/f1000research.19694.1
- 19 Marshansky V, Futai M. The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Curr Opin Cell Biol 2008; 20 (04) 415-426
- 20 Touret F, Gilles M, Barral K. et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. bioRxiv 2020; DOI: 10.1101/2020.04.03.02384625.
- 21 Wang H, Yang P, Liu K. et al. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 2008; 18 (02) 290-301
- 22 Sabolić I, Brown D, Verbavatz JM. et al. (+)-ATPases of renal cortical and medullary endosomes are differentially sensitive to Sch-28080 and omeprazole. Am J Physiol 1994; 266 (6 Pt 2) F868-F877
- 23 Sachs G, Prinz C, Loo D. et al. Gastric acid secretion: activation and inhibition. Yale J Biol Med 1994; 67 (3-4): 81-95
- 24 Brecher M, Schornberg KL, Delos SE. et al. Cathepsin cleavage potentiates the Ebola virus glycoprotein to undergo a subsequent fusion-relevant conformational change. J Virol 2012; 86: 364-372
- 25 Sobhy H. A review of functional motifs utilized by viruses. Proteomes 2016; 4 (01) 3
- 26 Watanabe SM, Ehrlich LS, Strickland M. et al. Selective targeting of virus replication by proton pump inhibitors. Sci Rep 2020; 10: 4003
- 27 Tabata K, Arimoto M, Arakawa M. et al. Unique Requirement for ESCRT factors in flavivirus particle formation on the endoplasmic reticulum. Cell Rep 2016; 16: 2339-2347
- 28 Irie T, Licata JM, McGettigan JP. et al. Budding of PPxY-containing rhabdoviruses is not dependent on host proteins TGS101 and VPS4A. J Virol 2004; 78: 2657-2665
- 29 George SN, Garcha DS, Mackay AJ. et al. Human rhinovirus infection during naturally occurring COPD exacerbations. Eur Respir J 2014; 44 (01) 87-96
- 30 Long J, Wright E, Molesti E. et al. Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry. Version 2. F1000Res 2015; 4: 30 DOI: 10.12688/f1000research.6085.2.
- 31 Sasaki T, Nakayama K, Yasuda H. et al. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc 2009; 57 (08) 1453-1457
- 32 Casanova C, Baudet JS, del Valle Velasco M. et al. Increased gastro-oesophageal reflux disease in patients with severe COPD. Eur Respir J 2004; 23 (06) 841-845
- 33 Su VY, Liao HF, Perng DW. et al. Proton pump inhibitors use is associated with a lower risk of acute exacerbation and mortality in patients with coexistent COPD and GERD. Int J Chron Obstruct Pulmon Dis 2018; 13: 2907-2915
- 34 Xiao F, Tang M, Zheng X. et al. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology 2020; 158: 1831-1833.e3
- 35 Aragão DS, Cunha TS, Andrade MCC. et al. Purification and characterization of angiotensin converting enzyme 2 (ACE2) from murine model of mesangial cell in culture. Int J Biol Macromol 2011; 49: 79-84
- 36 Liu J, Ji H, Zheng W. et al. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ 2010; 1 (01) 6 DOI: 10.1186/2042-6410-1-6.
- 37 Farrell CP, Morgan M, Rudolph DS. et al. Proton Pump Inhibitors Interfere With Zinc Absorption and Zinc Body Stores. Gastroenterol Res 2011; 4: 243-251
- 38 Bojkova D, McGreig JE, McLaughlin K. et al. SARS-CoV-2 and SARS-CoV differ in their cell tropism and drug sensitivity profiles. bioRxiv. 2020 DOI: 10.1101/2020.04.03.024257
- 39 Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil 2013; 19 (01) 25-35
- 40 US Food and Drug Administration. Prilosec Label – FDA. ttps://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022056s001019810s087lbl.pdf accessed on July 29 2020
- 41 Ozutemiz AO, Aydin HH, Isler M. et al. Effect of omeprazole on plasma zinc levels after oral zinc administration. Indian J Gastroenterol 2002; 21 (06) 216-218
- 42 Reeves PG, O’Dell BL. Effects of dietary zinc deprivation on the activity of angiotensin-converting enzyme in serum of rats and guinea pigs. J Nutr 1986; 116: 128-134
- 43 Speth R, Carrera E, Jean-Baptiste M. et al. Concentration-dependent effects of zinc on angiotensin-converting enzyme-2 activity (1067.4). The FASEB Journal 2014; 28 DOI: 10.1096/fasebj.28.1_supplement.1067.4.
- 44 Cao JW, Duan SY, Zhang HX. et al. Zinc deficiency promoted fibrosis via ROS and TIMP/MMPs in the myocardium of mice. Biol Trace Elem Res 2020; 196 (01) 145-152
- 45 Homolak J, Kodvanj I. Widely available lysosome targeting agents should be considered as potential therapy for COVID-19. Int J Antimicrob Agents 2020; 106044 DOI: 10.1016/j.ijantimicag.2020.106044.
- 46 Blanc F, Waechter C, Vogel T. et al. Interest of proton pump inhibitors in reducing the occurrence of COVID-19: A case-control study. Preprints 2020; DOI: 10.20944/preprints202005.0016.v1.
- 47 World Health Organization R&D Blueprint and COVID-19. 2020 https://www.who.int/teams/blueprint/covid-19 accessed on July 29, 2020
- 48 Almario CV, Chey WD, BMR Spiegel. Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors. Am J Gastroenterol. 2020 https://journals.lww.com/ajg/Documents/AJG-20-1811_R1(PUBLISH%20AS%20WEBPART).pdf, accessed on July 29, 2020
- 49 Luxenburger H, Sturm L, Biever P. et al. Treatment with proton pump inhibitors increases the risk of secondary infections and ARDS in hospitalized patients with COVID-19: coincidence or underestimated risk factor?. J Intern Med 2020; DOI: 10.1111/joim.13121.
- 50 Zhang X-Y, Wu H-B, Ling Y. et al. Analysis of the effect of proton pump inhibitors on the course of common COVID-19. medRxiv 2020; DOI: 10.1101/2020.06.07.20124776.
- 51 Taştemur Ş, Ataseven H. Is it possible to use Proton Pump Inhibitors in COVID-19 treatment and prophylaxis?. Medical Hypotheses 2020; 110018. DOI: 10.1016/j.mehy.2020.110018.
- 52 Aguila EJT, Cua IHY. Repurposed GI Drugs in the Treatment of COVID-19. Dig Dis Sci 2020; 65 (08) 2452-2453