Between two storms, vasoactive peptides or bradykinin underlie severity of COVID‐19?

Karamyan, Vardan T.

doi:10.14814/phy2.14796

Cited by 21 publications

(18 citation statements)

References 103 publications

(148 reference statements)

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“…Such multi-pathway target would be highly desired for stroke pharmacotherapy, since it is well-recognized that targeting one pathophysiological pathway is unlikely to be therapeutically effective in this complex disorder. If the therapeutic potential of Nln activators is confirmed in future studies, such molecules could become a new drug class for stroke therapy and perhaps other neurological disorders (Karamyan, 2019;Karamyan, 2021a). Hence, the identified dipeptides provide a chemical scaffold for the development of high-potency, drug-like molecules as research tools and potential drug leads.…”

Section: Discussionmentioning

confidence: 98%

Identification and Characterization of Two Structurally Related Dipeptides that Enhance Catalytic Efficiency of Neurolysin

Jayaraman

Kocot

Esfahani

et al. 2021

J Pharmacol Exp Ther

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Neurolysin (Nln) is a recently recognized endogenous mechanism functioning to preserve the brain from ischemic injury. To further understand the pathophysiological function of this peptidase in stroke and other neurological disorders, the present study was designed to identify small molecule activators of Nln.Using a computational approach, the structure of Nln was explored, followed by docking and in silico screening of ~140,000 molecules from the National Cancer Institute Developmental Therapeutics Program database. Top ranking compounds were evaluated in a Nln enzymatic assay, and two hit histidine-dipeptides were further studied in detail. The identified dipeptides enhanced the rate of synthetic substrate hydrolysis by recombinant (human and rat) and mouse brain-purified Nln in a concentrationdependent manner (micromolar A 50 and A max ≥ 300%), but had negligible effect on activity of closely related peptidases. Both dipeptides also enhanced hydrolysis of Nln endogenous substrates neurotensin, angiotensin I and bradykinin, and increased efficiency of the synthetic substrate hydrolysis (V max /K m ratio) in a concentration-dependent manner. The dipeptides and competitive inhibitor dynorphin A(1-13) did not affect each other's affinity for Nln, suggesting differing nature of their respective binding sites.Lastly, drug affinity responsive target stability (DARTS) and differential scanning fluorimetry (DSF) assays confirmed concentration-dependent interaction of Nln with the activator molecule. This is the first study demonstrating that Nln activity can be enhanced by small molecules, although the peptidic nature and low potency of the activators limit their application. The identified dipeptides provide a chemical scaffold to develop high-potency, drug-like molecules as research tools and potential drug leads. Significance statementThis study describes discovery of two molecules that selectively enhance activity of peptidase neurolysin (Nln)a newly recognized cerebroprotective mechanism in the post-stroke brain. The identified molecules will serve as a chemical scaffold for development of drug-like molecules to further study Nln, This article has not been copyedited and formatted. The final version may differ from this version.

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Section: Discussionmentioning

confidence: 98%

Identification and Characterization of Two Structurally Related Dipeptides that Enhance Catalytic Efficiency of Neurolysin

Jayaraman

Kocot

Esfahani

et al. 2021

J Pharmacol Exp Ther

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“…Furthermore, the interplay between BK and neurotensin (NT) or substance P (SP), as well as their cognate signaling pathways, has been identified as critical players in pathogenic mechanisms of COVID-19 (Karamyan 2021). The BK, NT, and SP could cause impairment of BBB under pathophysiological conditions (Al-Ahmad et al 2021), as well as are related to inflammation-induced complications of COVID-19 pathology (Karamyan 2021). Simultaneous inhibition of BK, NT, and SP systems would be therapeutically more advantageous rather than modulation of the BK mechanism alone.…”

Section: Bradykinin Pathway In the Pathogenesis Of Covid-19mentioning

confidence: 99%

“…According to Veerdonk et al (2020a, b) (van de Veerdonk et al 2020b), the pulmonary angioedema presented in COVID-19 patients may be associated with the release of kinins, resulting in a very high number of intensive care unit (ICU) admissions. Furthermore, COVID-19 severity has been associated with the upregulation of proinflammatory cytokines that could be stimulated by the BK cascade (Karamyan 2021). Therefore, blocking BK receptors might ameliorate COVID-19 complications by reducing kinin levels and, consequently, the inflammatory process (van de Veerdonk et al 2020b).…”

Section: Pharmacotherapies That Target Bk Dabk or B1 And B2 Receptors In The Treatment Of Covid-19mentioning

confidence: 99%

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Bradykinin-target therapies in SARS-CoV-2 infection: current evidence and perspectives

Silva

Araújo-Júnior

Silva-Júnior

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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Coronavirus disease 2019 (COVID-19) is a potentially fatal disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that preferentially infects the respiratory tract. Bradykinin (BK) is a hypotensive substance that recently emerged as one of the mechanisms to explain COVID-19-related complications. Concerning this, in this review, we try to address the complex link between BK and pathophysiology of COVID-19, investigating the role of this peptide as a potential target for pharmacological modulation in the management of SARS-CoV-2. The pathology of COVID-19 may be more a result of the BK storm than the cytokine storm, and which BK imbalance is a relevant factor in the respiratory disorders caused by SARS-CoV-2 infection. Regarding this, an interesting point of intervention for this disease is to modulate BK signaling. Some drugs, such as icatibant, ecallantide, and noscapine, and even a human monoclonal antibody, lanadelumab, have been studied for their potential utility in COVID-19 by modulating BK signaling. The interaction of the BK pathway and the involvement of cytokines such as IL-6 and IL1 may be key to the use of blockers, even if only as adjuvants. In fact, reduction of BK, mainly DABK, is considered a relevant strategy to improve clinical conditions of COVID-19 patients. In this context, despite the current unproven clinical efficacy, drugs repurposing that block B1 or B2 receptor activation have gained prominence for the treatment of COVID-19 in the world.

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“…Thus, ‘bradykinin storm’ is better referred to as ‘vasoactive peptide storm’. If these three peptides are inhibited, it can terminate the ‘vasoactive peptide storm’ and can better modulate the effects of COVID-19 [63] . MB may terminate the effects of bradykinin by inhibiting nitric oxide synthase inhibitor and promoting saturation of oxygen [64] , [65] .…”

Section: Possible Mechanisms Of Methylene Blue In Reducing Covid-19 Pathogenesismentioning

confidence: 99%

Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations

Dabholkar¹,

Gorantla²,

Dubey³

et al. 2021

Biomedicine & Pharmacotherapy

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The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the most recent coronaviruses, which has infected humans, and caused the disease COVID-19. The World Health Organization has declared COVID-19 as a pandemic in March 2020. The SARS-CoV-2 enters human hosts majorly via the respiratory tract, affecting the lungs first. In few critical cases, the infection progresses to failure of the respiratory system known as acute respiratory distress syndrome acute respiratory distress syndrome may be further associated with multi-organ failure and vasoplegic shock. Currently, the treatment of COVID-19 involves use of antiviral and anti-cytokine drugs. However, both the drugs have low efficacy because they cannot inhibit the production of free radicals and cytokines at the same time. Recently, some researchers have reported the use of methylene blue (MB) in COVID-19 management. MB has been used since a long time as a therapeutic agent, and has been approved by the US FDA for the treatment of other diseases. The additional advantage of MB is its low cost. MB is a safe drug when used in the dose of < 2 mg/kg. In this review, the applicability of MB in COVID-19 and its mechanistic aspects have been explored and compiled. The clinical studies have been explained in great detail. Thus, the potential of MB in the management of COVID-19 has been examined.

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Between two storms, vasoactive peptides or bradykinin underlie severity of COVID‐19?

Cited by 21 publications

References 103 publications

Identification and Characterization of Two Structurally Related Dipeptides that Enhance Catalytic Efficiency of Neurolysin

Identification and Characterization of Two Structurally Related Dipeptides that Enhance Catalytic Efficiency of Neurolysin

Bradykinin-target therapies in SARS-CoV-2 infection: current evidence and perspectives

Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations

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