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Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

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Drug Development Research
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David Gurwitz at Tel Aviv University
David Gurwitz
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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.
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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 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.
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 2002–2003
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;81:537–540. 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. ...
Carotid Body Size on CT Angiography in Patients With COVID-19 Pneumonia
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Purpose Many pathophysiological theories have been expressed regarding increased sympathetic activity along with respiratory failure in patients with COVID-19 pneumonia. In addition, the carotid bodies, which are directly related to increased blood oxygen levels and sympathetic activity, are known to be very rich in the angiotensin-converting enzyme 2 (ACE2) receptor, which the COVID-19 causative virus uses to enter the cell. Therefore, the probability of carotid bodies being affected in patients with COVID-19 pneumonia is quite high. Carotid bodies can be visualized with contrast-enhanced CT angiography (CTA), and we aimed to visualize possible carotid body enlargement in COVID-19 patients with CTA. Methods We retrospectively evaluated patients who were hospitalized for COVID-19 pneumonia during the pandemic in our hospital and who had CTA examinations at least 3 months after treatment. We drew a Region of Interest (ROI) from the periphery of both carotid bodies and measured the area from the widest part. Similarly, measurements were taken in the control group without a history of COVID-19, and the results of the two groups were compared statistically. Results We performed measurements on CTA images of 104 control subjects and 108 patients. The total carotid body area of the patients with COVID-19 pneumonia was 4.9 ± 3.7 mm ² , and the carotid body area of the control group was 3.7 ± 2.4 mm ² . In comparing the two groups, the carotid body area was found to be statistically significantly larger (p < 0.05) in patients with COVID-19 pneumonia. Conclusion The size of the carotid body was found to be larger in patients with COVID-19 pneumonia compared to the control group. This finding may indicate conditions that lead to the activation of carotid body chemo and baroreceptors, such as increased sympathetic activity and a decrease in blood oxygen pressure in patients with COVID-19 pneumonia. Apart from this, it may also be possible for the carotid body to be directly infected with the virus. More specific studies that shed light on this aspect are needed.
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Inflammation plays a fundamental role in the development and bidirectional association of di-verse diseases, such as periodontitis and type 2 diabetes mellitus (T2DM), which generates important clinical complications, where chronic exposure to high levels of blood glucose affects the repair process of periodontal tissues. Likewise, it has been observed that comorbidity, between these two diseases, influences the development of the COVID-19 disease towards a more severe course. However, there is currently very little scientific evidence on the relationship between periodontitis, T2DM and COVID-19 disease. This narrative review aims to provide an understanding of the current and most relevant aspects of the relationship between periodontitis, T2DM and COVID-19 disease. A narrative review was performed through a systematic search of published studies, without date restrictions, indexed in the electronic databases of PubMed, for the inclusion of articles in English, and LILACS for the inclusion of articles in Spanish. This review included different articles, which addressed the most important aspects to present a current perspective on the relationship and influence between periodontitis, T2DM and COVID-19 disease. Comorbidity between periodontitis and T2DM represents a greater risk of developing a more severe course of COVID-19 disease, because these three diseases share three important axes: a clinicopathological axis; an axis associated with glycemia, and an immunological axis associated with inflammation.
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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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Article
Full-text available
  • Mar 2025
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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. ...
The Use of ACE inhibitor/ARB in SARS-CoV-2 Patients: A Comprehensive Narrative Review
Article
Full-text available
  • Nov 2020
The three most common comorbidities that are associated with increased mortality in COVID-19 patients are Hypertension, Diabetes, and Cardiovascular disease, Angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARB) are the drugs most commonly prescribed for the management of these diseases. Recent experimental study in animals and humans have found that SARS-CoV-2 uses ACE2 as the receptors for entry. Moreover, in an animal study, the use of ACE inhibitor/ARB increases the level of ACE2 expression that can lead to increased SARS-CoV-2 infectivity. On the other side, some evidences suggest that the ACE2 receptor is not necessary for SARS-CoV-2 entry into the cell and suggested that there is a cofactor that play part. Experimental studies in humans also showed that there is no association between ACE inhibitor/ARB with SARS-CoV-2 infectivity and mortality. In conclusion, there is still insufficient data to stop the use of inhibitor/ARB in SARS-CoV-2 patients. Therefore, we suggested that in line with the recommendations from ESC and AHA/ACC, the use of these two drugs in SARS-CoV-2 patients with cardiovascular comorbidity should still be continued.
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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]. ...
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... 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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Article
Full-text available
  • Oct 2024
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Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia
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  • Mar 2020
The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.
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Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies
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The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
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Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia
Article
  • Feb 2020
The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.
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Potential Interventions for Novel Coronavirus in China: A Systemic Review
Article
  • Feb 2020
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.
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