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Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

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Abstract

At the time of writing this commentary (February 2020), the coronavirus COVID‐19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS‐CoV‐2 virus may take many months. Moreover, vaccines based on viral‐encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS‐CoV‐2 virus infections. This idea is based on observations that the angiotensin‐converting enzyme 2 (ACE2) very likely serves as the binding site for SARS‐CoV‐2, the strain implicated in the current COVID‐19 epidemic, similarly to strain SARS‐CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS‐CoV‐2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.
COMMENTARY
Angiotensin receptor blockers as tentative SARS-CoV-2
therapeutics
David Gurwitz
Department of Human Molecular Genetics and
Biochemistry, Sackler Faculty of Medicine, Tel-
Aviv University, Tel-Aviv, Israel
Correspondence
David Gurwitz, Department of Human
Molecular Genetics and Biochemistry, Sackler
Faculty of Medicine, Tel-Aviv University, Tel-
Aviv 69978, Israel.
Email: gurwitz@post.tau.ac.il
Abstract
At the time of writing this commentary (February 2020), the coronavirus COVID-19
epidemic has already resulted in more fatalities compared with the SARS and MERS
coronavirus epidemics combined. Therapeutics that may assist to contain its rapid
spread and reduce its high mortality rates are urgently needed. Developing vaccines
against the SARS-CoV-2 virus may take many months. Moreover, vaccines based on
viral-encoded peptides may not be effective against future coronavirus epidemics, as
virus mutations could make them futile. Indeed, new Influenza virus strains emerge
every year, requiring new immunizations. A tentative suggestion based on existing
therapeutics, which would likely be resistant to new coronavirus mutations, is to use
available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for
reducing the aggressiveness and mortality from SARS-CoV-2 virus infections. This
idea is based on observations that the angiotensin-converting enzyme 2 (ACE2) very
likely serves as the binding site for SARS-CoV-2, the strain implicated in the current
COVID-19 epidemic, similarly to strain SARS-CoV implicated in the 20022003
SARS epidemic. This commentary elaborates on the idea of considering AT1R
blockers as tentative treatment for SARS-CoV-2 infections, and proposes a research
direction based on datamining of clinical patient records for assessing its feasibility.
KEYWORDS
angiotensin-converting enzyme 2 (ACE2), AT1R blockers, COVID-19 epidemic, losartan,
SARS-CoV-2
At the time of writing this commentary (February 2020), the death toll
from the COVID-19 epidemic caused by coronavirus SARS-CoV-2,
which emerged in late December 2019 in Wuhan, China (World Health
Organization, 2019), has surpassed the combined death toll of the
SARS (Severe Acute Respiratory Syndrome) epidemic of 20022003
and the MERS (Middle East Respiratory Syndrome) epidemic of 2013
combined (Mahase, 2020). This epidemic seems to be spreading at an
exponential rate, with a doubling period of 1.8 days, and there are
fears that it might progress to pandemic scales (Cheng & Shan, 2020).
Yet, no SARS-CoV-2 therapeutics are presently available, albeit some
treatment options which await validation have been published, includ-
ing several broad spectrum antivirals such as favipiravir and remdesivir
(Beigel et al., 2019, Li & De Clercq, 2020), the anti-malaria drug chloro-
quine (Gao, Tian, & Yang, 2020), and a traditional Chinese herbal
formula (Luo et al., 2020). The ultimate solution is, obviously, develop-
ing a SARS-CoV-2 vaccine (Patel et al., 2020; Zhang & Liu, 2020).
However, vaccines for the SARS-CoV developed since its outbreak
18 years ago have not materialized to an approved product. This topic
has been reviewed in detail (de Wit, van Doremalen, Falzarano, &
Munster, 2016) and is beyond the scope of this brief commentary. In
addition, there have been concerns about vaccine-mediated enhance-
ment of disease, for example, due to pulmonary immunopathology
upon challenge with SARS-CoV (Tseng et al., 2012). Moreover, even
once a vaccine is approved for human use, high virus mutation rates
mean that new vaccines may need to be developed for each outbreak,
similarly to the situation with new annual influenza vaccines (Belongia
et al., 2017). Below, I describe an alternative option which, if proven to
be effective, would allow a rapid application in the clinic.
Received: 25 February 2020 Accepted: 27 February 2020
DOI: 10.1002/ddr.21656
Drug Dev Res. 2020;81:537540. wileyonlinelibrary.com/journal/ddr © 2020 Wiley Periodicals, Inc. 537
... Diseases such as hypertension, chronic lung disease, kidney diseases, congestive heart failure (CHF), diabetes mellitus, and obesity are associated with increased sympathetic nerve activity [18,19]. COVID-19 infection, on the other hand, may increase sympathetic discharge through emotional distress, changes in blood gases, immune/inflammatory factors, or angiotensin converting enzyme (ACE)1/ ACE2 imbalance, apart from the comorbidities listed above [20][21][22]. In either case, increased sympathetic activity in COVID-19 patients can be classified as short or long-term "post-COVID-19″Dysautonomia (DSN) [21]. ...
... Therefore, there are studies showing that the increase in sympathetic activity is proportional to the presence and disease severity in patients with COVID-19 pneumonia [21,43,44]. Patients with COVID-19 pneumonia may experience increased sympathetic discharge through respiratory failure, changes in blood gases, immune/ inflammatory factors, or angiotensin-converting enzyme (ACE)1/ ACE2 imbalance [20,45,46]. The increase in CB size in patients with COVID-19 pneumonia supports a possible functional relationship between CB size and increased sympathetic activity. ...
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... The clinical characteristics of the COVID-19 disease are very diverse, which can present from an asymptomatic state, or mild symptoms can manifest (Ullah et al., 2021); until progressing to pneumonia, developing acute respiratory distress syndrome (ARDS), multiple organ dysfunction and death (Ye et al., 2020). The pathophysiology of COVID-19 disease may not be limited exclusively to pulmonary manifestations, including pneumonia and ARDS , since SARS-CoV-2 is able to infect other cell types which express its binding receptor, angiotensin-converting enzyme (ACE)-2 (Muniyappa and Gubbi, 2020), such as cells of the upper respiratory system, alveolar epithelial cells in lungs, enterocytes, endothelial cells (Gurwitz, 2020), from heart (Zheng et al., 2020), tubular epithelium kidney (Diao et al., 2021) and pancreas , causing organspecific extrapulmonary clinical manifestations associated with harmful effects on many other systems of the human body, such as neurological, thrombotic, endocrine, cardiac, dermatological, hepatic, renal and gastrointestinal . Although it is known that the majority of people with COVID-19 do not develop symptoms or only have mild manifestations of the disease, approximately 14% of infected people develop the disease with a severe course (Zhou et al., 2020), where advanced age and some comorbidities, such as diabetes (Abdi et al., 2020), have been associated as potential risk factors for triggering more severe disease and death (Zhou et al., 2020). ...
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... While the pandemic in 2020 caused mortality and morbidity, it continues to be an epidemic that needs to addressed. Though there have been multiple modalities of treatment for COVID19, each approach has been riddled with lacunae [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. From a Biophysical perspective, (1) these nucleoside analogue inhibitors are hindered by the proof reading activity which can excise the incorporated inhibitors conferring resistance to SARS-CoV-2 [15,16]; (2) Cyano group substituted at the 1' position will sterically clash with side chain of Ser861 preventing translocation of RNA, and a possible mutation at this position may allow processing of RNA synthesis and thereby survival of this virus [17]. ...
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... Therefore, the protective role of ARB is suggested in SARS-CoV associated lung injury and gives rise to the hypothesis that rather than its inhibition, the primary activation of RAAS in cardiovascular patients is the reason they are more prone to a deleterious outcome. 34,35 In his study that showed increased mortality among COVID-19 positive patients with comorbidity hypertension, diabetes, or cardiovascular disease, Guan et al. 8 do not report the number of patients taking ACE inhibitors or ARB. ...
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... Both viruses preferentially infect the lungs and gastrointestinal tract. Studies of SARS-CoV-1 show the virus uses membrane-incorporated "spike" glycoprotein interactions with human angiotensin-converting enzyme 2 (ACE2) for cellular attachment and entry [11]. Mechanistically, this results in the upregulation of the NF-Kβ inflammatory signaling pathway, which (i) increases pro-inflammatory cytokine levels (TNF-α, IL-6, cyclooxygenase-2 [COX-2]); (ii) enhances immune cell infiltration into the lungs (in part due to increased levels of Monocyte Chemoattractant Protein 1 [MCP-1]); and raises levels of macrophagic polarity, shifting from the healing M2 phenotype to the proinflammatory M1 phenotype [6]. ...
... SARS-CoV-2'nin reseptör olarak insan (hACE2'yi kullandığını bildirmiştir. Birkaç çalışma aynı şekilde, yeni SARS-CoV-2'nin muhtemelen hACE2 reseptörüne bağlandığını, ancak orijinal SARS virus suşundan daha yüksek bir afinite ile bağlandığını göstermiştir [81,115,167,222,228]. Viral zarfın S proteinine maruz kalmasıyla konformasyonel modifikasyonu ve konak hücre membranı ile füzyon, hücre girişinin ilk aşamasını oluşturur. ...
... Hence, this counter regulatory axis provides benefits not only for the acute lung injury, but also in the cardiovascular system [42] [35]. Enhanced production of vasodilators angiotensin (1-7) [43] diminishes hypertension associated with angiotensin II, [44]. Conversely, the downregulation of ACE2 has been related to increased pressure load and has enlarged the size of the myocardium via the activation of AT1R mediated by angiotensin II [45]. ...
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... Some studies suggest that the ACE2 receptor availability could be influenced by antihypertensive drugs. For example, hypertensive patients treated with the AT1R antagonist showed higher urinary ACE2 levels 23 , and chronic AT1R blockade results in ACE2 upregulation in humans 24 . Corroborating these results, our study demonstrated that losartan and enalapril maleate treatment in primate kidney Vero cells, a common model for SARS-CoV-2 replication, led to the same upregulation. ...
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An outbreak of a novel coronavirus (COVID‐19 or 2019‐CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA virus infection and we have found that general treatments, coronavirus‐specific treatments, and antiviral treatments should be useful in fighting COVID‐19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID‐19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID‐19 if the infection is uncontrollable. This article is protected by copyright. All rights reserved.