-
1.
Hallmarks of Alpha- and Betacoronavirus non-structural protein 7+8 complexes.
Krichel, B, Bylapudi, G, Schmidt, C, Blanchet, C, Schubert, R, Brings, L, Koehler, M, Zenobi, R, Svergun, D, Lorenzen, K, et al
Science advances. 2021;(10)
-
-
Free full text
-
Abstract
Coronaviruses infect many different species including humans. The last two decades have seen three zoonotic coronaviruses, with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) causing a pandemic in 2020. Coronaviral non-structural proteins (nsps) form the replication-transcription complex (RTC). Nsp7 and nsp8 interact with and regulate the RNA-dependent RNA-polymerase and other enzymes in the RTC. However, the structural plasticity of nsp7+8 complexes has been under debate. Here, we present the framework of nsp7+8 complex stoichiometry and topology based on native mass spectrometry and complementary biophysical techniques of nsp7+8 complexes from seven coronaviruses in the genera Alpha- and Betacoronavirus including SARS-CoV-2. Their complexes cluster into three groups, which systematically form either heterotrimers or heterotetramers or both, exhibiting distinct topologies. Moreover, even at high protein concentrations, SARS-CoV-2 nsp7+8 consists primarily of heterotetramers. From these results, the different assembly paths can be pinpointed to specific residues and an assembly model proposed.
-
2.
Corona Virus Disease-19 pandemic: The gastroenterologists' perspective.
Dhar, J, Samanta, J, Kochhar, R
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2020;(3):220-231
-
-
Free full text
-
Abstract
The world is witnessing a serious public health threat in the wake of the third corona virus pandemic, a novel corona virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). The Corona Virus Disease-19 (COVID-19) is not limited to the respiratory system but has widespread involvement including the gastrointestinal (GI) tract and liver, with evidence of prolonged fecal shedding and feco-oral transmission. This finding has stirred up a hornet's nest of not only a newer modality of the spread of the virus but also a risk of the unpredictable duration of the infective potential of the shedders. We reviewed the literature on fecal shedding and possible implications on prevention and surveillance strategies. The pandemic is changing the management of underlying chronic diseases such as inflammatory bowel disease (IBD) and other diseases. Moreover, for the gastroenterologist, doing endoscopic procedures in this COVID-19 era poses a high risk of contamination, as it is an aerosol-generating procedure. There is a daily influx of data on this disease, and multiple societies are coming up with various recommendations. We provide a comprehensive review of all the reported GI manifestations of COVID-19 infection and the side effects of confounding drugs. We have summarized the management recommendations for diseases such as IBD with COVID-19 and nutritional recommendations and provided a concise review of the endoscopy guidelines by the various societies. This review provides a comprehensive account and a lucid guide covering various aspects of gastroenterology practice during this COVID-19 pandemic.
-
3.
A Trial of Favipiravir and Hydroxychloroquine combination in Adults Hospitalized with moderate and severe Covid-19: A structured summary of a study protocol for a randomised controlled trial.
Bosaeed, M, Mahmoud, E, Hussein, M, Alharbi, A, Alsaedy, A, Alothman, A, Aljeraisy, M, Alqahtani, H, Nashabat, M, Almutairi, B, et al
Trials. 2020;(1):904
Abstract
OBJECTIVES The selected combination was based on limited evidence clinically and in vitro on the efficacy of the Favipiravir and Hydroxychloroquine in SARS-CoV-2. The two medications were listed in many guidelines as treatment options and ongoing trials assessing their efficacy and safety. Thus, we want to prove the clinical effectiveness of the combination as therapy. TRIAL DESIGN This is an Open label, multicenter, randomized controlled clinical trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. It is a multicenter trial that will compare Favipiravir plus Hydroxychloroquine combination (experimental arm) to a control arm. PARTICIPANTS All study procedures will be conducted in eight centres in Saudia Arabia: King Abdulaziz Medical City National Guard Health Affairs in Riyadh. King Abdulaziz Hospital - Al Ahsa, Saudi Arabia AlMadina General Hospital, Madnia, Saudi Arabia Al-Qatif Central Hospital, Saudi Arabia Imam Abdulrahman Al Faisal Hospital, Dammam, Saudi Arabia King Abdulaziz Medical City, Jeddah, Saudi Arabia King Abdulaziz Hospital, Makkah, Saudi Arabia Imam Abdulrahman Alfaisal Hospital, Riyadh, Saudi Arabia Inclusion Criteria • Should be at least 18 years of age, • Male or nonpregnant female, • Diagnosed with COVID-19 by PCR confirmed SARS-coV-2 viral infection. • Able to sign the consent form and agree to clinical samples collection (or their legal surrogates if subjects are or become unable to make informed decisions).. • Moderate or Severe COVID-19, defined as oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or significant clinical symptoms that require hospital admission. • patients had to be enrolled within 10 days of disease onset. Exclusion Criteria • Patients who are pregnant or breastfeeding. • Will be transferred to a non-study site hospital or discharged from hospital within 72 hours. • Known sensitivity/allergy to hydroxychloroquine or Favipiravir • Current use of hydroxychloroquine for another indication • Prior diagnosis of retinopathy • Prior diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency • Major comorbidities increasing the risk of study drug including: i. Hematologic malignancy, ii. Advanced (stage 4-5) chronic kidney disease or dialysis therapy, iii. Known history of ventricular arrhythmias, iv. Current use of drugs that prolong the QT interval, Severe liver damage (Child-Pugh score ≥ C, AST> 5 times the upper limit), HIV. • The investigator believes that participating in the trial is not in the best interests of the patient, or the investigator considers unsuitable for enrollment (such as unpredictable risks or subject compliance issues). • Clinical prognostic non-survival, palliative care, or in deep coma and no have response to supportive treatment within three hours of admission • Patient with irregular rhythm • Patient with a history of heart attack (myocardial infarction) • Patient with a family history of sudden death from heart attack before the age of 50 • Take other drugs that can cause prolonged QT interval • Patient who is receiving immunosuppressive therapy (cyclosporin) which cannot be switched to another agent or adjusted while using the investigational drug • Gout/history of Gout or hyperuricemia (above the ULN), hereditary xanthinuria or xanthine calculi of the urinary tract. INTERVENTION AND COMPARATOR The treatment intervention would be for a maximum of 10 days from randomization and it would be as follows: Favipiravir for 10 days: Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10 days) Hydroxychloroquine for 5 days: (400mg) twice daily on day 1; for days 2-5 (200mg) twice daily. Reference Comparator Therapy: Standard of care is defined as: Treatment that is accepted by medical experts as a proper treatment for Covid-19 disease. Standard care comprised of, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, extracorporeal membrane oxygenation (ECMO), and antiviral therapy except Favipiravir. Also, it may include intravenous fluids and medications for symptoms relief . MAIN OUTCOMES The primary endpoint is the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first (14 days from Randomization). RANDOMISATION Eligible participants will be randomized in a 1:1 ratio to either the combination group (Favipiravir and Hydroxychloroquine) or a control group. The patients will be randomized utilizing Web based data entry System with a stratification based on the centre and the ICU admission. BLINDING (MASKING): This is an Open label study and only the analyst will be blinded during the study conduct. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Under the classical two arm parallel design the total effective sample sizes needed is 472 subjects (236 subjects per group). TRIAL STATUS Protocol version 3.1 (dated 11 Aug 2020), and currently recruitment is ongoing. The date recruitment started was May 21, 2020 and the investigators anticipate the trial will finish recruiting by the end of December 2020. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04392973 , 19 May 2020 FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
-
4.
Using All-Atom Potentials to Refine RNA Structure Predictions of SARS-CoV-2 Stem Loops.
Bergonzo, C, Szakal, AL
International journal of molecular sciences. 2020;(17)
Abstract
A considerable amount of rapid-paced research is underway to combat the SARS-CoV-2 pandemic. In this work, we assess the 3D structure of the 5' untranslated region of its RNA, in the hopes that stable secondary structures can be targeted, interrupted, or otherwise measured. To this end, we have combined molecular dynamics simulations with previous Nuclear Magnetic Resonance measurements for stem loop 2 of SARS-CoV-1 to refine 3D structure predictions of that stem loop. We find that relatively short sampling times allow for loop rearrangement from predicted structures determined in absence of water or ions, to structures better aligned with experimental data. We then use molecular dynamics to predict the refined structure of the transcription regulatory leader sequence (TRS-L) region which includes stem loop 3, and show that arrangement of the loop around exchangeable monovalent potassium can interpret the conformational equilibrium determined by in-cell dimethyl sulfate (DMS) data.
-
5.
Candidate drugs against SARS-CoV-2 and COVID-19.
McKee, DL, Sternberg, A, Stange, U, Laufer, S, Naujokat, C
Pharmacological research. 2020;:104859
-
-
Free full text
-
Abstract
Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.
-
6.
ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome.
Devaux, CA, Rolain, JM, Raoult, D
Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2020;(3):425-435
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged in Chinese people in December 2019 and has currently spread worldwide causing the COVID-19 pandemic with more than 150,000 deaths. In order for a SARS-CoV like virus circulating in wild life for a very long time to infect the index case-patient, a number of conditions must be met, foremost among which is the encounter with humans and the presence in homo sapiens of a cellular receptor allowing the virus to bind. Recently it was shown that the SARS-CoV-2 spike protein, binds to the human angiotensin I converting enzyme 2 (ACE2). This molecule is a peptidase expressed at the surface of lung epithelial cells and other tissues, that regulates the renin-angiotensin-aldosterone system. Humans are not equal with respect to the expression levels of the cellular ACE2. Moreover, ACE2 polymorphisms were recently described in human populations. Here we review the most recent evidence that ACE2 expression and/or polymorphism could influence both the susceptibility of people to SARS-CoV-2 infection and the outcome of the COVID-19 disease. Further exploration of the relationship between the virus, the peptidase function of ACE2 and the levels of angiotensin II in SARS-CoV-2 infected patients should help to better understand the pathophysiology of the disease and the multi-organ failures observed in severe COVID-19 cases, particularly heart failure.
-
7.
Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19).
Subir, R, Jagat J, M, Kalyan K, G
Diabetes & metabolic syndrome. 2020;(5):1225-1229
-
-
Free full text
-
Abstract
BACKGROUND AND AIMS Morbidity and mortality from coronavirus disease 2019 (COVID-19) is higher among people with diabetes mellitus (DM), hypertension, and cardiovascular disease (CVD). Statins are used in the majority of people with DM and CVD. This mini-review discusses the current understanding of benefit-risk ratio of use of statins in COVID-19. METHODS We searched PubMed database using specific keywords related to our aims till June 12, 2020. Full text of relevant articles published in English language were retrieved and reviewed. RESULTS Statins, with their immunomodulatory, anti-inflammatory, anti-thrombotic, and anti-oxidant properties, have the potential to reduce severity of lung injury in, and mortality from, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) infections. Statin-induced upregulation of angiotensin-converting enzyme-2 (ACE2) has the potential to reduce lung injury from excess angiotensin II. By disrupting lipid rafts, statins have the potential to reduce viral entry into cells. However, benefit-risk ratio of its complex interaction with MYD88 gene expression on outcomes in COVID-19, and the putative role of low serum LDL cholesterol in increasing severity of SARS-CoV2 infection need further clarification. CONCLUSIONS People with COVID-19, who are already on statins for an underlying co-morbid condition, should continue on it unless there are specific contraindications. De-novo use of statins in people with COVID-19 with no underlying co-morbidity might be beneficial but awaits substantiation in clinical trials; till that time, de novo use of statins in COVID 19 should be limited to a clinical trial setting.
-
8.
Obesity and COVID-19: A Perspective from the European Association for the Study of Obesity on Immunological Perturbations, Therapeutic Challenges, and Opportunities in Obesity.
Goossens, GH, Dicker, D, Farpour-Lambert, NJ, Frühbeck, G, Mullerova, D, Woodward, E, Holm, JC
Obesity facts. 2020;(4):439-452
Abstract
Accumulating evidence suggests that obesity is a major risk factor for the initiation, progression, and outcomes of coronavirus disease 2019 (COVID-19). The European Association for the Study of Obesity (EASO), as a scientific and medical society dedicated to the promotion of health and well-being, is greatly concerned about the concomitant obesity and COVID-19 pandemics and their impact on health and society at large. In this perspective, we will address the inherent immunological perturbations and alterations in the renin-angiotensin-aldosterone system in patients with obesity and COVID-19, and discuss how these impairments may underlie the increased susceptibility and more detrimental outcomes of COVID-19 in people with obesity. Clearly, this has important implications for preventive measures, vaccination, and future therapeutic strategies to combat COVID-19. Furthermore, we will highlight important knowledge gaps and provide suggestions for future research and recommendations for policy actions. Since many new reports on COVID-19 rapidly appear, the present perspective should be seen as a focus for discussion to drive forward further understanding, research initiatives, and clinical management of COVID-19.
-
9.
Interpretation of the Traditional Chinese Medicine portion of the diagnosis and treatment protocol for corona virus disease 2019 (Trial Version 7).
Song, P, Zhao, L, Li, X, Su, J, Jiang, Z, Song, B, Liu, W, Tang, S, Lei, Y, Ding, Q, et al
Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan. 2020;(3):497-508
Abstract
The TCM protocol in the Diagnosis and Treatment Protocol for corona virus disease 2019 (COVID-19) (Trial Version 7) has been updated from previous versions. The protocol was formulated under the direct leadership of the National Administration of Traditional Chinese Medicine, based on the experience of a panel of experts, supported by evidence from fever clinics and from the outcomes of emergency (EM) observation rooms and inpatients throughout China (especially in Wuhan, Hubei Province) in combination with the latest scientific research results and data. The present interpretation of the TCM protocol is based on an overall understanding of the revised content, and aims to guide and standardize its clinical application to provide a reference for clinicians.
-
10.
Chronic Inflammation in the Context of Everyday Life: Dietary Changes as Mitigating Factors.
Margină, D, Ungurianu, A, Purdel, C, Tsoukalas, D, Sarandi, E, Thanasoula, M, Tekos, F, Mesnage, R, Kouretas, D, Tsatsakis, A
International journal of environmental research and public health. 2020;(11)
Abstract
The lifestyle adopted by most people in Western societies has an important impact on the propensity to metabolic disorders (e.g., diabetes, cancer, cardiovascular disease, neurodegenerative diseases). This is often accompanied by chronic low-grade inflammation, driven by the activation of various molecular pathways such as STAT3 (signal transducer and activator of transcription 3), IKK (IκB kinase), MMP9 (matrix metallopeptidase 9), MAPK (mitogen-activated protein kinases), COX2 (cyclooxigenase 2), and NF-Kβ (nuclear factor kappa-light-chain-enhancer of activated B cells). Multiple intervention studies have demonstrated that lifestyle changes can lead to reduced inflammation and improved health. This can be linked to the concept of real-life risk simulation, since humans are continuously exposed to dietary factors in small doses and complex combinations (e.g., polyphenols, fibers, polyunsaturated fatty acids, etc.). Inflammation biomarkers improve in patients who consume a certain amount of fiber per day; some even losing weight. Fasting in combination with calorie restriction modulates molecular mechanisms such as m-TOR, FOXO, NRF2, AMPK, and sirtuins, ultimately leads to significantly reduced inflammatory marker levels, as well as improved metabolic markers. Moving toward healthier dietary habits at the individual level and in publicly-funded institutions, such as schools or hospitals, could help improving public health, reducing healthcare costs and improving community resilience to epidemics (such as COVID-19), which predominantly affects individuals with metabolic diseases.