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The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system.
Eur Heart J Cardiovasc Pharmacother. 2020 09 01; 6(5):317-325.EH

Abstract

The SARS-CoV-2 pandemic is a healthcare crisis caused by insufficient knowledge applicable to effectively combat the virus. Therefore, different scientific discovery strategies need to be connected, to generate a rational treatment which can be made available as rapidly as possible. This relies on a solid theoretical understanding of the mechanisms of SARS-CoV-2 infection and host responses, which is coupled to the practical experience of clinicians that are treating patients. Because SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), targeting ACE2 to prevent such binding seems an obvious strategy to combat infection. However, ACE2 performs its functions outside the cell and was found to enter the cell only by angiotensin II type 1 receptor (AT1R)-induced endocytosis, after which ACE2 is destroyed. This means that preventing uptake of ACE2 into the cell by blocking AT1R would be a more logical approach to limit entry of SARS-CoV-2 into the cell. Since ACE2 plays an important protective role in maintaining key biological processes, treatments should not disrupt the functional capacity of ACE2, to counterbalance the negative effects of the infection. Based on known mechanisms and knowledge of the characteristics of SARS-CoV we propose the hypothesis that the immune system facilitates SARS-CoV-2 replication which disrupts immune regulatory mechanisms. The proposed mechanism by which SARS-CoV-2 causes disease immediately suggests a possible treatment, since the AT1R is a key player in this whole process. AT1R antagonists appear to be the ideal candidate for the treatment of SARS-CoV-2 infection. AT1R antagonists counterbalance the negative consequences of angiotesnin II and, in addition, they might even be involved in preventing the cellular uptake of the virus without interfering with ACE2 function. AT1R antagonists are widely available, cheap, and safe. Therefore, we propose to consider using AT1R antagonists in the treatment of SARS-CoV-2.

Authors+Show Affiliations

Microbiology and System Biology, Netherlands Organisation for Applied Scientific Research, The Hague, The Netherlands.Microbiology and System Biology, Netherlands Organisation for Applied Scientific Research, The Hague, The Netherlands.Vascular Medicine, Amsterdam UMC, Academic Medical Center Amsterdam, Amsterdam, The Netherlands. Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.Faculty of Health Medicine and Life Sciences, University of Maastricht, Maastricht, The Netherlands.Cardiology, Amsterdam UMC, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.Vascular Medicine, Amsterdam UMC, Academic Medical Center Amsterdam, Amsterdam, The Netherlands. Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32464637

Citation

Offringa, Annette, et al. "The Mechanistic Overview of SARS-CoV-2 Using Angiotensin-converting Enzyme 2 to Enter the Cell for Replication: Possible Treatment Options Related to the Renin-angiotensin System." European Heart Journal. Cardiovascular Pharmacotherapy, vol. 6, no. 5, 2020, pp. 317-325.
Offringa A, Montijn R, Singh S, et al. The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system. Eur Heart J Cardiovasc Pharmacother. 2020;6(5):317-325.
Offringa, A., Montijn, R., Singh, S., Paul, M., Pinto, Y. M., & Pinto-Sietsma, S. J. (2020). The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system. European Heart Journal. Cardiovascular Pharmacotherapy, 6(5), 317-325. https://doi.org/10.1093/ehjcvp/pvaa053
Offringa A, et al. The Mechanistic Overview of SARS-CoV-2 Using Angiotensin-converting Enzyme 2 to Enter the Cell for Replication: Possible Treatment Options Related to the Renin-angiotensin System. Eur Heart J Cardiovasc Pharmacother. 2020 09 1;6(5):317-325. PubMed PMID: 32464637.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system. AU - Offringa,Annette, AU - Montijn,Roy, AU - Singh,Sandeep, AU - Paul,Martin, AU - Pinto,Yigal M, AU - Pinto-Sietsma,Sara-Joan, PY - 2020/04/16/received PY - 2020/04/25/revised PY - 2020/05/07/accepted PY - 2020/5/29/pubmed PY - 2020/9/24/medline PY - 2020/5/29/entrez KW - Angiotensin receptor blockers KW - Angiotensin-converting enzyme 2 KW - COVID-19 KW - Coronavirus KW - Renin–angiotensin–aldosterone system SP - 317 EP - 325 JF - European heart journal. Cardiovascular pharmacotherapy JO - Eur Heart J Cardiovasc Pharmacother VL - 6 IS - 5 N2 - The SARS-CoV-2 pandemic is a healthcare crisis caused by insufficient knowledge applicable to effectively combat the virus. Therefore, different scientific discovery strategies need to be connected, to generate a rational treatment which can be made available as rapidly as possible. This relies on a solid theoretical understanding of the mechanisms of SARS-CoV-2 infection and host responses, which is coupled to the practical experience of clinicians that are treating patients. Because SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), targeting ACE2 to prevent such binding seems an obvious strategy to combat infection. However, ACE2 performs its functions outside the cell and was found to enter the cell only by angiotensin II type 1 receptor (AT1R)-induced endocytosis, after which ACE2 is destroyed. This means that preventing uptake of ACE2 into the cell by blocking AT1R would be a more logical approach to limit entry of SARS-CoV-2 into the cell. Since ACE2 plays an important protective role in maintaining key biological processes, treatments should not disrupt the functional capacity of ACE2, to counterbalance the negative effects of the infection. Based on known mechanisms and knowledge of the characteristics of SARS-CoV we propose the hypothesis that the immune system facilitates SARS-CoV-2 replication which disrupts immune regulatory mechanisms. The proposed mechanism by which SARS-CoV-2 causes disease immediately suggests a possible treatment, since the AT1R is a key player in this whole process. AT1R antagonists appear to be the ideal candidate for the treatment of SARS-CoV-2 infection. AT1R antagonists counterbalance the negative consequences of angiotesnin II and, in addition, they might even be involved in preventing the cellular uptake of the virus without interfering with ACE2 function. AT1R antagonists are widely available, cheap, and safe. Therefore, we propose to consider using AT1R antagonists in the treatment of SARS-CoV-2. SN - 2055-6845 UR - https://www.unboundmedicine.com/medline/citation/32464637/The_mechanistic_overview_of_SARS_CoV_2_using_angiotensin_converting_enzyme_2_to_enter_the_cell_for_replication:_possible_treatment_options_related_to_the_renin_angiotensin_system_ L2 - https://academic.oup.com/ehjcvp/article-lookup/doi/10.1093/ehjcvp/pvaa053 DB - PRIME DP - Unbound Medicine ER -