(searched for: doi:10.20944/preprints202004.0457.v1)
Journal of Infection and Public Health, Volume 13, pp 1868-1877; doi:10.1016/j.jiph.2020.09.015
Quinones are reactive to proteins containing cysteine residues and the main protease in Covid-19 contains an active site that includes Cys145. Embelin, a quinone natural product, is known to have antiviral activity against influenza and hepatitis B. Preliminary studies by our group also indicate its ability to inhibit HSV-1 in cultured cells. Docking and DFT methods applied to the protease target. a mechanism for this inhibition of the SARS-CoV-2 Mpro protease is described, specifically due to formation of a covalent bond between S(Cys145) and an embelin C(carbonyl). This is assisted by two protein amino acids (1) N(imidazole-His41) which is able to capture H[S(Cys145)] and (2) HN(His163), which donates a proton to embelin O(carbonyl) forming an OH moiety that results in inhibition of the viral protease. A similar process is also seen with the anti-inflammatory drugs methyl prednisolone and dexamethasone, used for Covid-19 patients. Methyl prednisolone and dexamethasone are methide quinones, and possess only one carbonyl moiety, instead of two for embelin. Additional consideration was given to another natural product, emodin, recently patented against Covid-19, as well as some therapeutic quinones, vitamin K, suspected to be involved in Covid-19 action, and coenzyme Q10. All show structural similarities with embelin, dexamethasone and methyl prednisolone results. Our data on embelin and related quinones indicate that these natural compounds may represent a feasible, strategic tool against Covid-19.
Published: 9 November 2020
SARS-CoV-2 causes remarkably variable disease from asymptomatic individuals to respiratory insufficiency and coagulopathy. Vitamin K deficiency was recently found to associate with clinical outcome in a cohort of COVID-19 patients. Vitamin D has been hypothesized to reduce disease susceptibility by modulating inflammation, yet little is known about its role in disease severity. Considering the critical interaction between vitamin K and vitamin D in calcium and elastic fiber metabolism, we determined vitamin D status in the same cohort of 135 hospitalized COVID-19 patients by measuring blood 25(OH)D levels. We found no difference in vitamin D status between those with good and poor outcome (defined as intubation and/or death). Instead, we found vitamin D sufficient persons (25(OH)D >50 nmol/L) had accelerated elastic fiber degradation compared to those with mild deficiency (25(OH)D 25-50 nmol/L). Based on these findings, we hypothesize that vitamin D might have both favorable anti-inflammatory and unfavorable pro-calcification effects during COVID-19 and that vitamin K might compensate for the latter.
Medical alphabet; doi:10.33667/2078-5631-2020-20-54-59
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International Journal of Molecular Sciences, Volume 21; doi:10.3390/ijms21145094
A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19.
Therapeutic Advances in Gastroenterology, Volume 13; doi:10.1177/1756284820974914
The novel coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus has spread rapidly across the globe, culminating in major global morbidity and mortality. As such, there has been a rapid escalation in scientific and clinical activity aimed at increasing our comprehension of this virus. This volume of work has led to early insights into risk factors associated with severity of disease, and mechanisms that underpin the virulence and dynamics involved in viral transmission. These insights ultimately may help guide potential therapeutics to reduce the human, economic and social impact of this pandemic. Importantly, the gastrointestinal (GI) tract has emerged as an important organ influencing propensity to, and potentially severity of, COVID-19 infection. Furthermore, the gut microbiome has been linked to a variety of risk factors for COVID-19 infection, and manipulation of the gut microbiome is an attractive potential therapeutic target for a number of diseases. While data profiling the gut microbiome in COVID-19 infection to date are limited, they support the possibility of several routes of interaction between COVID-19, the gut microbiome, angiotensin converting enzyme 2 (ACE-2) expression in the small bowel and colon and gut inflammation. This article will explore the evidence that implicates the gut microbiome as a contributing factor to the pathogenesis, severity and disease course of COVID-19, and speculate about the gut microbiome’s capability as a therapeutic avenue against COVID-19. Lay summary It has been noted that certain baseline gut profiles of COVID-19 patients are associated with a more severe disease course, and the gut microbiome impacts the disease course of several contributory risk factors to the severity of COVID-19. A protein called ACE-2, which is found in the small intestine among other sites, is a key receptor for COVID-19 virus entry; there is evidence that the gut microbiome influences ACE-2 receptor expression, and hence may play a role in influencing COVID-19 infectivity and disease severity. Furthermore, the gut microbiome plays a significant role in immune regulation, and hence may be pivotal in influencing the immune response to COVID-19. In terms of understanding COVID-19 treatments, the gut microbiome is known to interact with several drug classes being used to target COVID-19 and should be factored into our understanding of how patients respond to treatment. Importantly, our understanding of the role of the gut microbiome in COVID-19 infection remains in its infancy, but future research may potentially aid our mechanistic understanding of viral infection, and new ways in which we might approach treating it.