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Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology?

Discovering therapeutics for COVID‐19 is a priority. Besides high‐throughput screening of compounds, candidates might be identified based on their known mechanisms of action and current understanding of the SARs‐CoV‐2 life cycle. Using this approach, proton pump (PPIs) and sodium‐hydrogen exchanger...

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Autor principal: Conrad, Kirk P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762781/
https://www.ncbi.nlm.nih.gov/pubmed/33369281
http://dx.doi.org/10.14814/phy2.14649
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author Conrad, Kirk P.
author_facet Conrad, Kirk P.
author_sort Conrad, Kirk P.
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description Discovering therapeutics for COVID‐19 is a priority. Besides high‐throughput screening of compounds, candidates might be identified based on their known mechanisms of action and current understanding of the SARs‐CoV‐2 life cycle. Using this approach, proton pump (PPIs) and sodium‐hydrogen exchanger inhibitors (NHEIs) emerged, because of their potential to inhibit the release of extracellular vesicles (EVs; exosomes and/or microvesicles) that could promote disease progression, and to directly disrupt SARs‐CoV‐2 pathogenesis. If EVs exacerbate SARs‐CoV‐2 infection as suggested for other viruses, then inhibiting EV release by PPIs/NHEIs should be beneficial. Mechanisms underlying inhibition of EV release by these drugs remain uncertain, but may involve perturbing endosomal pH especially of multivesicular bodies where intraluminal vesicles (nascent exosomes) are formed. Additionally, PPIs might inhibit the endosomal sorting complex for transport machinery involved in EV biogenesis. Through perturbing endocytic vesicle pH, PPIs/NHEIs could also impede cleavage of SARs‐CoV‐2 spike protein by cathepsins necessary for viral fusion with the endosomal membrane. Although pulmonary epithelial cells may rely mainly on plasma membrane serine protease TMPRSS2 for cell entry, PPIs/NHEIs might be efficacious in ACE2‐expressing cells where viral endocytosis is the major or a contributing entry pathway. These pharmaceutics might also perturb pH in the endoplasmic reticulum‐Golgi intermediate and Golgi compartments, thereby potentially disrupting viral assembly and glycosylation of spike protein/ACE2, respectively. A caveat, however, is that facilitation not inhibition of avian infectious bronchitis CoV pathogenesis was reported in one study after increasing Golgi pH. Envelope protein‐derived viroporins contributed to pulmonary edema formation in mice infected with SARs‐CoV. If similar pathogenesis occurs with SARs‐CoV‐2, then blocking these channels with NHEIs could ameliorate disease pathogenesis. To ascertain their potential efficacy, PPIs/NHEIs need evaluation in cell and animal models at various phases of SARs‐CoV‐2 infection. If they prove to be therapeutic, the greatest benefit might be realized with the administration before the onset of severe cytokine release syndrome.
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spelling pubmed-77627812020-12-28 Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology? Conrad, Kirk P. Physiol Rep Review Articles Discovering therapeutics for COVID‐19 is a priority. Besides high‐throughput screening of compounds, candidates might be identified based on their known mechanisms of action and current understanding of the SARs‐CoV‐2 life cycle. Using this approach, proton pump (PPIs) and sodium‐hydrogen exchanger inhibitors (NHEIs) emerged, because of their potential to inhibit the release of extracellular vesicles (EVs; exosomes and/or microvesicles) that could promote disease progression, and to directly disrupt SARs‐CoV‐2 pathogenesis. If EVs exacerbate SARs‐CoV‐2 infection as suggested for other viruses, then inhibiting EV release by PPIs/NHEIs should be beneficial. Mechanisms underlying inhibition of EV release by these drugs remain uncertain, but may involve perturbing endosomal pH especially of multivesicular bodies where intraluminal vesicles (nascent exosomes) are formed. Additionally, PPIs might inhibit the endosomal sorting complex for transport machinery involved in EV biogenesis. Through perturbing endocytic vesicle pH, PPIs/NHEIs could also impede cleavage of SARs‐CoV‐2 spike protein by cathepsins necessary for viral fusion with the endosomal membrane. Although pulmonary epithelial cells may rely mainly on plasma membrane serine protease TMPRSS2 for cell entry, PPIs/NHEIs might be efficacious in ACE2‐expressing cells where viral endocytosis is the major or a contributing entry pathway. These pharmaceutics might also perturb pH in the endoplasmic reticulum‐Golgi intermediate and Golgi compartments, thereby potentially disrupting viral assembly and glycosylation of spike protein/ACE2, respectively. A caveat, however, is that facilitation not inhibition of avian infectious bronchitis CoV pathogenesis was reported in one study after increasing Golgi pH. Envelope protein‐derived viroporins contributed to pulmonary edema formation in mice infected with SARs‐CoV. If similar pathogenesis occurs with SARs‐CoV‐2, then blocking these channels with NHEIs could ameliorate disease pathogenesis. To ascertain their potential efficacy, PPIs/NHEIs need evaluation in cell and animal models at various phases of SARs‐CoV‐2 infection. If they prove to be therapeutic, the greatest benefit might be realized with the administration before the onset of severe cytokine release syndrome. John Wiley and Sons Inc. 2020-12-25 /pmc/articles/PMC7762781/ /pubmed/33369281 http://dx.doi.org/10.14814/phy2.14649 Text en © 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review Articles
Conrad, Kirk P.
Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology?
title Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology?
title_full Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology?
title_fullStr Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology?
title_full_unstemmed Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology?
title_short Might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate SARs‐CoV‐2 pathophysiology?
title_sort might proton pump or sodium‐hydrogen exchanger inhibitors be of value to ameliorate sars‐cov‐2 pathophysiology?
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762781/
https://www.ncbi.nlm.nih.gov/pubmed/33369281
http://dx.doi.org/10.14814/phy2.14649
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