The coronavirus helicase is an essential enzyme required for viral replication/transcription pathways. Structural studies revealed a sulphate moiety that interacts with key residues within the nucleotide-binding site of the helicase. Compounds with a sulphoxide or a sulphone moiety could interfere with these interactions and consequently inhibit the enzyme. The molecular operating environment (MOE) was used to dock 189 sulphoxide and sulphone-containing FDA-approved compounds to the nucleotide-binding site. Zafirlukast, a leukotriene receptor antagonist used to treat chronic asthma, achieved the lowest docking score at -8.75 kcals/mol. The inhibitory effect of the compounds on the SARS-CoV-2 helicase dsDNA unwinding activity was tested by a FRET-based assay. Zafirlukast was the only compound to inhibit the enzyme (IC50 = 16.3 µM). The treatment of Vero E6 cells with 25 µM zafirlukast prior to SARS-CoV-2 infection decreased the cytopathic effects of SARS-CoV-2 significantly. These results suggest that zafirlukast alleviates SARS-CoV-2 pathogenicity by inhibiting the viral helicase and impairing the viral replication/transcription pathway. Zafirlukast could be clinically developed as a new antiviral treatment for SARS-CoV-2 and other coronavirus diseases. This discovery is based on molecular modelling, in vitro inhibition of the SARS-CoV helicase activity and cell-based SARS-CoV-2 viral replication.

Discovery of Zafirlukast as a novel SARS-CoV-2 helicase inhibitor using in silico modelling and a FRET-based assay.

Increasing environmental distress is associated with a growing asthma incidence; no treatments are available but montelukast (MTK)—an antagonist of the cysteinyl leukotrienes receptor 1—is widely used in the management of symptoms among adults and children. Recently, new molecular targets have been identified and MTK has been proposed for repurposing in other therapeutic applications, with several ongoing clinical trials. The proposed applications include neuroinflammation control, which could be explored in some neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (AD and PD). However, this drug has been associated with an increasing number of reported neuropsychiatric adverse drug reactions (ADRs). Besides, and despite being on the market since 1998, MTK metabolism is still poorly understood and the mechanisms underlying neuropsychiatric ADRs remain unknown. We review the role of MTK as a modulator of leukotriene pathways and systematize the current knowledge about MTK metabolism. Known toxic effects of MTK are discussed, and repurposing applications are presented comprehensively, with a focus on AD and PD.

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Leukotrienes vs. Montelukast—Activity, Metabolism, and Toxicity Hints for Repurposing

The risk of aluminium exposure to humans is very high as it may get into the human body through excessive dietary contaminants, inhalation of fine particulate matter, or through parenteral routes as a vaccine adjuvant and so forth. The increased level of aluminium in brain tissue has been shown to be associated with several neurodegenerative and neurotoxic adverse effects, including AD. However, the exact mechanism of aluminium‐induced neurotoxicity is still unclear. Therefore, our study aimed to investigate the mechanism of neurotoxic and neurodegenerative effects through in vitro exposure of aluminium in rat glioma C6 cell line. The findings of our study have indicated that aluminium chloride exposure may lead to alteration in acetylcholine levels, increased oxidative imbalance and induction of molecular structural and functional markers of neuronal inflammation. This study also demonstrated that aluminium exposure may lead to the induction of caspase‐3 along with apoptotic cell death and a significant increase in amyloid‐beta and hyperphosphorylated tau levels in C6 cells. Thus, this study may provide a mechanistic understanding of the regulation of neuroinflammatory and neurodegenerative biomarkers due to aluminium exposure.

Exposure of aluminium to C6 glioma cells modulates molecular and functional neurotoxic markers

Abstract Aluminum is an environmentally abundant potential neurotoxic agent that may result in oxidative damage to a range of cellular biomarkers. The potential sources of aluminum accumulation in the body include drinking water, food, medicines, vaccines, and aluminum cookware utensils, etc. The accumulation of aluminum in the brain is reported to be associated with cholinergic dysfunction, oxidative stress and neuronal damage, which may ultimately cause Alzheimer’s disease. Since chronic exposure to aluminum leads to its accumulation in the brain, so this study was done by a long-term (24 weeks) low dose (20 mg/kg) oral exposure of aluminum chloride in rats. In this chronic model, we have evaluated the major hallmarks of Alzheimer’s disease including amyloid-beta (Aβ1–42) and phosphorylated-tau (p231-tau) protein in brain tissue. Furthermore, we evaluated the level of acetyl cholinesterase activity, inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and oxidative stress biomarkers in the rat brain in this model. The neurobehavioral parameters were also assessed in animals by using spontaneous locomotor activity, passive avoidance, rotarod test and novel object recognition test to evaluate alteration in learning, memory and muscle co-ordination. We found that chronic oral exposure to aluminum chloride causes a significant increase in structural hallmarks such as Aβ1–42 and p231-tau levels along with pro-inflammatory cytokines (TNF-α and IL-6), oxidative stress, and a decrease in antioxidant markers such as GSH and catalase in the brain tissue. These biomarkers significantly affected neurobehavioral parameters in animals. This study provides a mechanistic understanding of chronic aluminum-induced neuronal toxicity in the brain with relevance to Alzheimer’s disease.

Chronic oral exposure of aluminum chloride in rat modulates molecular and functional neurotoxic markers relevant to Alzheimer’s disease

The coronavirus disease 2019 (COVID-19) (SARS-Cov-2) has caused a worldwide, sudden and substantial increase in hospitalizations for pneumonia with multiorgan problems. An important issue is also that there is still no unified standard for the diagnosis and treatment of COVID-19. Substantial vascular events are significant accompaniments to lung complications in COVID-19 patients. Various papers have now also shown the significance of thromboelastrography (TEG®) as point-of-care technology to determine the levels of coagulopathy (both clotting and bleeding) in COVID-19, in managing COVID-19 patients. Here we present two treatment protocols that may used to treat thrombotic and bleeding or thrombocytopenia pathologies. Both the protocols use clinical parameters like D-dimer and CRP, as well as the TEG®, to closely follow the daily clotting propensity of COVID-19 patients. We conclude by suggesting that the treatment of COVID-19 patients, should be based on a combination of blood biomarkers, and results from point-of-care analyses like the TEG®. Such a combination approach closely follow the physiological responses of the immune system, the haematological, as well as the coagulation system, in real-time.

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A decision-tree approach to treat platelet hyperactivity and anomalous blood clotting in acute COVID-19 patients

Background The coronavirus disease-19 (COVID-19) pandemic is a serious devastating disease and has posed a global health emergency. So far, there is not any specific therapy approved till date to control the clinical symptoms of the disease. Remdesivir has been approved by the FDA as an emergency clinical therapy. But it may not be effective alone to control the disease as it can only control the viral replication in the host. Summary This article summarizes the possible therapeutic potential and benefits of using montelukast, a cysteinyl leukotriene 1 (CysLT1) receptor antagonist, to control COVID-19 pathophysiology. Montelukast has shown anti-inflammatory effects, reduced cytokine production, improvement in post-infection cough production and other lung complications. Key Messages: Recent reports clearly indicate a distinct role of CysLT-regulated cytokines and immunological signaling in COVID-19. Thus, montelukast may have a clinical potential to control lung pathology during COVID-19.

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Possible Therapeutic Potential of Cysteinyl Leukotriene Receptor Antagonist Montelukast in Treatment of SARS-CoV-2-Induced COVID-19.

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases [1,2]. The disease affects a global population of over 40 million, along with a burden of 7.7 million new cases ever...

https://www.tandfonline.com/doi/pdf/10.1080/14728222.2021.1924151

Mangaldeep Dey

Papers

Possible Therapeutic Potential of Cysteinyl Leukotriene Receptor Antagonist Montelukast in Treatment of SARS-CoV-2-Induced COVID-19.

Inhibition of MK2 kinase as a potential therapeutic target to control neuroinflammation in Alzheimer's disease.