scholarly journals The Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19

2020 ◽  
Author(s):  
Robert Hoffman ◽  
Robert S. Kania ◽  
Mary A. Brothers ◽  
Jay F. Davies ◽  
Rose A. Ferre ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Research Effort ◽  
The Novel ◽  
Protein Cleavage ◽  
X Ray Crystallography ◽  
Processing Step ◽  
Covalent Inhibitors ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus ◽  
Further Development

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins which are cleaved at specific sites by a cysteine 3C-like protease (3CLpro) in a post-translational processing step that is critical for coronavirus replication. The 3CLpro sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CLpro with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.

scholarly journals The Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19

2020 ◽  
Author(s):  
Robert Hoffman ◽  
Robert S. Kania ◽  
Mary A. Brothers ◽  
Jay F. Davies ◽  
Rose A. Ferre ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Research Effort ◽  
The Novel ◽  
Protein Cleavage ◽  
X Ray Crystallography ◽  
Processing Step ◽  
Covalent Inhibitors ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus ◽  
Further Development

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins which are cleaved at specific sites by a cysteine 3C-like protease (3CLpro) in a post-translational processing step that is critical for coronavirus replication. The 3CLpro sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CLpro with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.

scholarly journals X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

2020 ◽  
Author(s):  
Linlin Zhang ◽  
Daizong Lin ◽  
Xinyuanyuan Sun ◽  
Katharina Rox ◽  
Rolf Hilgenfeld
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Atypical Pneumonia ◽  
The Novel ◽  
Replication Complex ◽  
X Ray ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Novel Coronavirus ◽  
Further Development

AbstractA novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 Å resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-Å crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

scholarly journals Reproducibility and reporting practices in COVID-19 preprint manuscripts

2020 ◽  
Author(s):  
Josh Sumner ◽  
Leah Haynes ◽  
Sarah Nathan ◽  
Cynthia Hudson-Vitale ◽  
Leslie D. McIntosh
Keyword(s):  
Best Practices ◽  
Research Effort ◽  
Open Science ◽  
The Novel ◽  
Important Research ◽  
Public Officials ◽  
Reporting Practices ◽  
Share Data ◽  
Funding Information ◽  
Novel Coronavirus

AbstractThe novel coronavirus, COVID-19, has sparked an outflow of scientific research seeking to understand the virus, its spread, and best practices in prevention and treatment. If this international research effort is going to be as swift and effective as possible, it will need to rely on a principle of open science. When researchers share data, code, and software and generally make their work as transparent as possible, it allows other researchers to verify and expand upon their work. Furthermore, it allows public officials to make informed decisions. In this study, we analyzed 535 preprint articles related to COVID-19 for eight transparency criteria and recorded study location and funding information. We found that individual researchers have lined up to help during this crisis, quickly tackling important public health questions, often without funding or support from outside organizations. However, most authors could improve their data sharing and scientific reporting practices. The contrast between researchers’ commitment to doing important research and their reporting practices reveals underlying weaknesses in the research community’s reporting habits, but not necessarily their science.

scholarly journals Identification of SARS-CoV2 Main Protease Coldspots Suitable for Drug Targeting

2020 ◽  
Author(s):  
Navaneethakrishnan Krishnamoorthy ◽  
Khalid Fakhro
Keyword(s):  
Active Site ◽  
Missense Mutations ◽  
The Novel ◽  
X Ray ◽  
X Ray Crystallography ◽  
Main Protease ◽  
New Perspective ◽  
Function Relationship ◽  
Novel Coronavirus ◽  
Relationship Of

Abstract Most attempts to target the novel coronavirus SARS-CoV2 are focusing on the main protease (Mpro) 1,2. We already have access to high resolution 3D-structures of the SARS-CoV2 Mpro, which were developed with inhibitors as co-crystals using X-ray crystallography 3-9. However, >19,000 missense mutations in the Mpro have already been reported 10. The mutations encompassing 282 amino acid positions and these “hotspots” might change the Mpro structure and activity, potentially rendering novel antivirals and vaccines ineffective. Here we identified 24 mutational “coldspots” that have resisted mutation since the virus was first detected. We compared the structure-function relationship of these coldspots with several SARS-CoV2 Mpro X-ray crystal structures. We found that three coldspot residues (Leu141, Phe185 and Gln192) help to form the active site, while six (Gly2, Arg4, Tyr126, Lys137, Leu141 and Leu286) contribute to dimer formation that is required for Mpro activity. Importantly, seven coldpots are conserved among other coronaviruses and available on the surface of the active site and at the dimer interface for targeting. The identification and short list of these coldspots offers a new perspective to target the SARS-CoV2 Mpro while avoiding mutation-based drug resistance.

scholarly journals COVID-19 vaccine hesitancy is associated with beliefs on the origin of the novel coronavirus in the UK and Turkey

2020 ◽  
pp. 1-3 ◽  
Author(s):  
Gul Deniz Salali ◽  
Mete Sefa Uysal
Keyword(s):  
Online Survey ◽  
Vaccine Development ◽  
Research Effort ◽  
Vaccine Hesitancy ◽  
Effective Vaccine ◽  
The Novel ◽  
Natural Origin ◽  
The Public ◽  
Novel Coronavirus ◽  
The Uk

Abstract Background Much research effort is focused on developing an effective vaccine for combatting coronavirus disease 2019 (COVID-19). Vaccine development itself, however, will not be enough given that a sufficient amount of people will need to be vaccinated for widespread immunity. Vaccine hesitancy is on the rise, varies across countries, and is associated with conspiratorial worldview. Given the rise in COVID-19-related conspiracy theories, we aimed to examine the levels of COVID-19 vaccine hesitancy and its association with beliefs on the origin of the novel coronavirus in a cross-cultural study. Methods We conducted an online survey in the UK (N = 1088) and Turkey (N = 3936), and gathered information on participants' willingness to vaccinate for a potential COVID-19 vaccine, beliefs on the origin of the novel coronavirus, and several behavioural and demographic predictors (such as anxiety, risk perception, government satisfaction levels) that influence vaccination and origin beliefs. Results In all, 31% of the participants in Turkey and 14% in the UK were unsure about getting themselves vaccinated for a COVID-19 vaccine. In both countries, 3% of the participants rejected to be vaccinated. Also, 54% of the participants in Turkey and 63% in the UK believed in the natural origin of the novel coronavirus. Believing in the natural origin significantly increased the odds of COVID-19 vaccine acceptance. Conclusions Our results point at a concerning level of COVID-19 vaccine hesitancy, especially in Turkey, and suggest that wider communication of the scientific consensus on the origin of the novel coronavirus with the public may help future campaigns targeting COVID-19 vaccine hesitancy.

scholarly journals Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19; a Fiction, Hope or Hype? An Updated Review

2020 ◽  
Author(s):  
Sultan Saghir ◽  
Naif AlGabri ◽  
Mahmoud Alagawany ◽  
Youssef Attia ◽  
Salem Alailay ◽  
...  
Keyword(s):  
Research Effort ◽  
Case Fatality ◽  
Current Evidence ◽  
The Novel ◽  
Comprehensive Overview ◽  
Novel Coronavirus ◽  
Antiviral Medications ◽  
Selection Of

In December 2019, the novel coronavirus disease pandemic (COVID-19) that began in China had infected more than 56 million individuals worldwide and accounted for more than 1.344.000 fatalities. With the dawn of this novel coronavirus (SARS-CoV-2), there was a requirement to select potential therapies that might effectively kill the virus, accelerate the recovery, or decrease the case fatality rate. Besides the currently available antiviral medications for HIV and HCV, the chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without azithromycin has been repurposed in China and was recommended by the National Health Commission, China in mid-February 2020. By this time, the selection of this regimen was based on its efficacy against the previous SARS-CoV-1 virus and its potential to inhibit viral replication of the SARS-CoV-2 in vitro. There was a shortage of robust clinical proof about the effectiveness of this regimen against the novel SARS-CoV-2. Therefore, extensive research effort has been made by several researchers worldwide to investigate whether this regimen is safe and effective for the management of COVID-19. This review article provides a comprehensive overview of the CQ/HCQ regimen. It summarizes the evaluating data from in vitro studies and clinical studies either for the protection or the treatment against SARS-CoV-2. There is a sharp difference of opinion about the role of CQ/HCQ regimen in treatment of COVID-19. The literature data are controversial and contradictory due to the diverse study design, population selection, dosage, regimen, and outcome measures. Current evidence from the two largest randomized-controlled trials (recovery and solidarity) suggests that the HCQ regimen does not decrease COVID-19 patients’ mortality. However, conflicting data were published from observational studies showing that the drug might be sufficient. Therefore, more investigations are needed to emphasize these findings.

Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

2020 ◽  
Author(s):  
Micael Davi Lima de Oliveira ◽  
Kelson Mota Teixeira de Oliveira
Keyword(s):  
World Health Organisation ◽  
World Health ◽  
Lung Cells ◽  
The Novel ◽  
High Modulation ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Viral Receptors ◽  
Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

SARS-COV2 virus and Coronavirus disease (COVID-19)

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 977-982
Author(s):  
Mohamed J. Saadh ◽  
Bashar Haj Rashid M ◽  
Roa’a Matar ◽  
Sajeda Riyad Aldibs ◽  
Hala Sbaih ◽  
...  
Keyword(s):  
Close Contact ◽  
Antiviral Agents ◽  
Health Concern ◽  
The Novel ◽  
Global Public Health ◽  
Fatal Disease ◽  
Mild Disease ◽  
Life Threatening ◽  
Novel Coronavirus

SARS-COV2 virus causes Coronavirus disease (COVID-19) and represents the causative agent of a potentially fatal disease that is of great global public health concern. The novel coronavirus (2019) was discovered in 2019 in Wuhan, the market of the wet animal, China with viral pneumonia cases and is life-threatening. Today, WHO announces COVID-19 outbreak as a pandemic. COVID-19 is likely to be zoonotic. It is transmitted from bats as intermediary animals to human. Also, the virus is transmitted from human to human who is in close contact with others. The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is nearly supportive; the role of antiviral agents is yet to be established. The SARS-COV2 virus spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. In this article, we aimed to summarize the transmission, symptoms, pathogenesis, diagnosis, treatment, and vaccine to control the spread of this fatal disease.

Coronavirus: Towards controlling of the pandemic - Indian scenario

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 462-468
Author(s):  
Latika kothari ◽  
Sanskruti Wadatkar ◽  
Roshni Taori ◽  
Pavan Bajaj ◽  
Diksha Agrawal
Keyword(s):  
Control Measures ◽  
The Novel ◽  
Medical Treatments ◽  
Health Crisis ◽  
The Public ◽  
Infection Control Measures ◽  
The Social ◽  
Asking Questions ◽  
The Government ◽  
Novel Coronavirus

Coronavirus disease 2019 (COVID-19) is a communicable infection caused by the novel coronavirus resulting in severe acute respiratory syndrome coronavirus 2 (SARS-CoV). It was recognized to be a health crisis for the general population of international concern on 30th January 2020 and conceded as a pandemic on 11th March 2020. India is taking various measures to fight this invisible enemy by adopting different strategies and policies. To stop the COVID-19 from spreading, the Home Affairs Ministry and the health ministry, of India, has issued the nCoV 19 guidelines on travel. Screening for COVID-19 by asking questions about any symptoms, recent travel history, and exposure. India has been trying to get testing kits available. The government of India has enforced various laws like the social distancing, Janata curfew, strict lockdowns, screening door to door to control the spread of novel coronavirus. In this pandemic, innovative medical treatments are being explored, and a proper vaccine is being hunted to deal with the situation. Infection control measures are necessary to prevent the virus from further spreading and to help control the current situation. Thus, this review illustrates and explains the criteria provided by the government of India to the awareness of the public to prevent the spread of COVID-19.

Association and treatment of diabetes in patients affected by Covid-19

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1198-1201
Author(s):  
Syed Yasir Afaque
Keyword(s):  
Diabetes Mellitus ◽  
Prognostic Value ◽  
Heart Diseases ◽  
The Novel ◽  
The World ◽  
Treatment Of Diabetes ◽  
Coronavirus Infection ◽  
Composite Outcomes ◽  
Novel Coronavirus ◽  
The Impact

In December 2019, a unique coronavirus infection, SARS-CoV-2, was first identified in the province of Wuhan in China. Since then, it spread rapidly all over the world and has been responsible for a large number of morbidity and mortality among humans. According to a latest study, Diabetes mellitus, heart diseases, Hypertension etc. are being considered important risk factors for the development of this infection and is also associated with unfavorable outcomes in these patients. There is little evidence concerning the trail back of these patients possibly because of a small number of participants and people who experienced primary composite outcomes (such as admission in the ICU, usage of machine-driven ventilation or even fatality of these patients). Until now, there are no academic findings that have proven independent prognostic value of diabetes on death in the novel Coronavirus patients. However, there are several conjectures linking Diabetes with the impact as well as progression of COVID-19 in these patients. The aim of this review is to acknowledge about the association amongst Diabetes and the novel Coronavirus and the result of the infection in such patients.

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