scholarly journals Allosteric perspective on the mutability and druggability of the SARS-CoV-2 Spike protein

2021 ◽  
Author(s):  
Zhen Wah Tan ◽  
Wei-Ven Tee ◽  
Firdaus Samsudin ◽  
Enrico Guarnera ◽  
Peter J Bond ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Rna Viruses ◽  
Viral Proteins ◽  
Spike Protein ◽  
Endemic Disease ◽  
Structure And Dynamics ◽  
Recent Developments ◽  
Comprehensive Picture ◽  
Allosteric Mechanisms

Recent developments in the SARS-CoV-2 pandemic point to its inevitable transformation into an endemic disease, urging both diagnostics of emerging variants of concern (VOCs) and design of the variant-specific drugs in addition to vaccine adjustments. Exploring the structure and dynamics of the SARS-CoV-2 Spike protein, we argue that the high mutability characteristic of RNA viruses coupled with the remarkable flexibility and dynamics of viral proteins result in a substantial involvement of allosteric mechanisms. While allosteric effects of mutations should be considered in predictions and diagnostics of new VOCs, allosteric drugs advantageously avoid escaping mutations via non-competitive inhibition originating from many alternative distal locations. The exhaustive allosteric signalling and probing maps provide a comprehensive picture of allostery in the Spike protein, making it possible to locate sites of potential mutations that could work as new VOCs 'drivers', and to determine binding patches that may be targeted by newly developed allosteric drugs.

scholarly journals Mutational Frequencies of SARS-CoV-2 Genome during the Beginning Months of the Outbreak in USA

Pathogens ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 565 ◽  
Author(s):  
Neha Kaushal ◽  
Yogita Gupta ◽  
Mehendi Goyal ◽  
Svetlana F. Khaiboullina ◽  
Manoj Baranwal ◽  
...  
Keyword(s):  
Viral Genome ◽  
Nucleocapsid Protein ◽  
Human Population ◽  
Rna Viruses ◽  
Viral Proteins ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Virus Propagation ◽  
The Us ◽  
Viral Genes

SARS-CoV-2 has spread very quickly from its first reported case on 19 January 2020 in the United Stated of America, leading WHO to declare pandemic by 11 March 2020. RNA viruses accumulate mutations following replication and passage in human population, which prompted us to determine the rate and the regions (hotspots) of the viral genome with high rates of mutation. We analyzed the rate of mutation accumulation over a period of 11 weeks (submitted between 19th January to 15 April 2020) in USA SARS-CoV-2 genome. Our analysis identified that majority of the viral genes accumulated mutations, although with varying rates and these included NSP2, NSP3, RdRp, helicase, Spike, ORF3a, ORF8, and Nucleocapsid protein. Sixteen mutations accumulated in Spike protein in which four mutations are located in the receptor binding domain. Intriguingly, we identified a fair number of viral proteins (NSP7, NSP9, NSP10, NSP11, Envelop, ORF6, and ORF7b proteins), which did not accumulate any mutation. Limited changes in these proteins may suggest that they have conserved functions, which are essential for virus propagation. This provides a basis for a better understanding of the genetic variation in SARS-CoV-2 circulating in the US, which could help in identifying potential therapeutic targets for controlling COVID-19.

scholarly journals Inhibition of HECT E3 ligases as potential therapy for COVID-19

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Giuseppe Novelli ◽  
◽  
Jing Liu ◽  
Michela Biancolella ◽  
Tonino Alonzi ◽  
...  
Keyword(s):  
World Wide ◽  
Therapeutic Strategy ◽  
Rna Viruses ◽  
Family Members ◽  
E3 Ligase ◽  
Direct Interaction ◽  
Spike Protein ◽  
E3 Ligases ◽  
Antiviral Effects ◽  
Novel Biomarkers

AbstractSARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

scholarly journals Repurposing of Drugs Targeted Against COVID-19 Spike Receptor for Treatment: An In silico Approach

2021 ◽  
Vol 11 (5) ◽  
pp. 13740-13753
Keyword(s):  
Rna Viruses ◽  
Neurological Diseases ◽  
Data Bank ◽  
Spike Protein ◽  
The Novel ◽  
Converting Enzyme ◽  
Enzyme Protein ◽  
Receptor Structure ◽  
Ligand Structure ◽  
Biological Field

An escalating pandemic by the novel SARS-CoV2 is spreading across the globe at a rate. An urgent need for therapy is needed. Initially, the virus appeared first in Wuhan, China, and later approximately in 187 countries worldwide. Coronaviruses are causative of respiratory as well as neurological diseases in humans. The novel zoonotic disease-causing coronaviruses are single-stranded RNA viruses. The coronavirus's outer structure consists of spike protein made up of glycoproteins, which binds to ACE (Angiotensin Converting Enzyme) protein when infected in humans. In the current study, 37 compounds that are already used in the biological field as anti-viral compounds are observed with bioinformatics tools. The repurposing drugs are docked against the spike receptor by molecular Docking. The ligand structure and the receptor structure are retrieved from Protein Data Bank. Patch dock server is an open freeware available for docking procedures. The results include acceleration and score of matched properties showing the feasibility of working the drug against SARS-nCoV. For the visualization of the final docked product, PyMOL and RasWin software’s are used. The scores of each ligand docked against the receptor show the compatibility working against the COVID-19 disease.

scholarly journals Neutron scattering in the biological sciences: progress and prospects

2018 ◽  
Vol 74 (12) ◽  
pp. 1129-1168 ◽  
Author(s):  
Rana Ashkar ◽  
Hassina Z. Bilheux ◽  
Heliosa Bordallo ◽  
Robert Briber ◽  
David J. E. Callaway ◽  
...  
Keyword(s):  
Biological Sciences ◽  
National Science Foundation ◽  
High Performance ◽  
Simulation Models ◽  
Deuterium Labeling ◽  
Maximum Information ◽  
Structure And Dynamics ◽  
Recent Developments ◽  
High Performance Computer ◽  
Computer Simulation Models

The scattering of neutrons can be used to provide information on the structure and dynamics of biological systems on multiple length and time scales. Pursuant to a National Science Foundation-funded workshop in February 2018, recent developments in this field are reviewed here, as well as future prospects that can be expected given recent advances in sources, instrumentation and computational power and methods. Crystallography, solution scattering, dynamics, membranes, labeling and imaging are examined. For the extraction of maximum information, the incorporation of judicious specific deuterium labeling, the integration of several types of experiment, and interpretation using high-performance computer simulation models are often found to be particularly powerful.

scholarly journals Distinct modes of manipulation of rice auxin response factor OsARF17 by different plant RNA viruses for infection

2020 ◽  
Vol 117 (16) ◽  
pp. 9112-9121 ◽  
Author(s):  
Hehong Zhang ◽  
Lulu Li ◽  
Yuqing He ◽  
Qingqing Qin ◽  
Changhai Chen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Rna Viruses ◽  
Rna Virus ◽  
Viral Proteins ◽  
Plant Viruses ◽  
Auxin Response Factor ◽  
Auxin Signaling ◽  
Response Factor ◽  
Auxin Response

Plant auxin response factor (ARF) transcription factors are an important class of key transcriptional modulators in auxin signaling. Despite the well-studied roles of ARF transcription factors in plant growth and development, it is largely unknown whether, and how, ARF transcription factors may be involved in plant resistance to pathogens. We show here that two fijiviruses (double-stranded RNA viruses) utilize their proteins to disturb the dimerization of OsARF17 and repress its transcriptional activation ability, while a tenuivirus (negative-sense single-stranded RNA virus) directly interferes with the DNA binding activity of OsARF17. These interactions impair OsARF17-mediated antiviral defense. OsARF17 also confers resistance to a cytorhabdovirus and was directly targeted by one of the viral proteins. Thus, OsARF17 is the common target of several very different viruses. This suggests that OsARF17 plays a crucial role in plant defense against different types of plant viruses, and that these viruses use independently evolved viral proteins to target this key component of auxin signaling and facilitate infection.

scholarly journals High-Potency Polypeptide-based Interference for Coronavirus Spike Glycoproteins

2021 ◽  
Author(s):  
Qinghua Wang ◽  
Jianpeng Ma ◽  
Adam Acevedo
Keyword(s):  
Amino Acid Sequence Identity ◽  
Natural Infection ◽  
Viral Proteins ◽  
Spike Protein ◽  
High Potency ◽  
Viral Pathogens ◽  
Native Sequence ◽  
Virion Envelope ◽  
Novel Concept ◽  
Spike Proteins

Abstract The world is experiencing an unprecedented coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 spike protein-based vaccines are currently the main preventive agent to fight against the virus. However, several variants with extensive mutations in SARS-CoV-2 spike proteins have emerged. Some of these variants exhibited increased replication, higher transmission and virulence, and were partially resistant to antibody neutralization from natural infection or vaccination. With over 130 million confirmed cases and widespread vaccination around the globe, the emergence of new escape SARS-CoV-2 variants could be accelerated. New therapeutics insensitive to mutations are thus urgently needed. Here we have developed an inhibitor based on SARS-CoV-2 spike protein that potently reduced pseudovirus infectivity by limiting the level of SARS-CoV-2 spike proteins on virion envelope. Most importantly, the inhibitor was equally effective against other coronavirus spike proteins that shared as low as 35% amino-acid sequence identity, underscoring its extreme tolerance to mutations. The small-sized inhibitor would also allow simple delivery by, for instance, nasal spray. We expect the inhibitor reported here to be an invaluable aid to help end COVID-19 pandemic. Furthermore, the use of a partial native sequence or its homologues to interfere with the functions of the native protein represents a novel concept for targeting other viral proteins in combating against important viral pathogens.

scholarly journals Unravelling roles of error-prone DNA polymerases in shaping cancer genomes

Oncogene ◽  
2021 ◽  
Author(s):  
Cyrus Vaziri ◽  
Igor B. Rogozin ◽  
Qisheng Gu ◽  
Di Wu ◽  
Tovah A. Day
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Polymerase ◽  
Genome Stability ◽  
Dna Polymerases ◽  
The Cancer Genome Atlas ◽  
Cancer Genomes ◽  
Recent Developments ◽  
Comprehensive Picture

AbstractMutagenesis is a key hallmark and enabling characteristic of cancer cells, yet the diverse underlying mutagenic mechanisms that shape cancer genomes are not understood. This review will consider the emerging challenge of determining how DNA damage response pathways—both tolerance and repair—act upon specific forms of DNA damage to generate mutations characteristic of tumors. DNA polymerases are typically the ultimate mutagenic effectors of DNA repair pathways. Therefore, understanding the contributions of DNA polymerases is critical to develop a more comprehensive picture of mutagenic mechanisms in tumors. Selection of an appropriate DNA polymerase—whether error-free or error-prone—for a particular DNA template is critical to the maintenance of genome stability. We review different modes of DNA polymerase dysregulation including mutation, polymorphism, and over-expression of the polymerases themselves or their associated activators. Based upon recent findings connecting DNA polymerases with specific mechanisms of mutagenesis, we propose that compensation for DNA repair defects by error-prone polymerases may be a general paradigm molding the mutational landscape of cancer cells. Notably, we demonstrate that correlation of error-prone polymerase expression with mutation burden in a subset of patient tumors from The Cancer Genome Atlas can identify mechanistic hypotheses for further testing. We contrast experimental approaches from broad, genome-wide strategies to approaches with a narrower focus on a few hundred base pairs of DNA. In addition, we consider recent developments in computational annotation of patient tumor data to identify patterns of mutagenesis. Finally, we discuss the innovations and future experiments that will develop a more comprehensive portrait of mutagenic mechanisms in human tumors.

scholarly journals Future and recent developments in the retail vegetable category – a value chain and food systems approach

2020 ◽  
pp. 1-24
Author(s):  
Fredrik Fernqvist ◽  
Caroline Göransson
Keyword(s):  
Value Chain ◽  
Food Systems ◽  
Food System ◽  
Systems Approach ◽  
Single Case ◽  
Current Trends ◽  
A Value ◽  
Future Challenges ◽  
Recent Developments ◽  
Comprehensive Picture

In this study, the value chain perspective was combined with a food systems approach to assess food system responses in the value chain and external drivers from environmental and socioeconomic perspectives. The research object was the Swedish value chain for vegetables, with the aim of providing a comprehensive picture of current trends and drivers and identifying future developments important for vegetable growers, producer organizations, wholesalers and retailers. The empirical data is based on in-depth interviews with key-decision makers in the Swedish value chain, constituting a single case. The point of departure is that key actors in this chain, from producer organizations to retailers, can provide a comprehensive picture on the category’s past development and future directions. A combined food systems and value chain approach has been applied. Drivers and chain responses have been identified and categorized into six main categories related to: (1) health; (2) consumer interest for food and variation; (3) convenience; (4) origin; (5) sustainability; and (6) urbanization. Value chain responses and future challenges as well as aspects on value chain dynamics and sustainability issues in the food system are presented and discussed.

scholarly journals Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment

2020 ◽  
Author(s):  
Varalakshmi Velagacherla ◽  
Akhil Suresh ◽  
Chetan H Mehta ◽  
Yogendra Nayak ◽  
Usha Y Nayak
Keyword(s):  
Md Simulations ◽  
Viral Proteins ◽  
Spike Protein ◽  
Protein Targets ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Protease ◽  
Multiple Protein ◽  
Approved Drugs ◽  
Viral Target ◽  
Selection Of

Abstract Background: Coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is now a pandemic which began in Wuhan province of China. Drug discovery teams around the globe are in a race to develop a medicine for its management. For a novel molecule to enter into the market it takes time and the ideal way is to exploit the already approved drugs and repurpose them to use therapeutically.Methods: In this work, we have attempted to screen selected molecules that have shown an affinity towards multiple protein targets of COVID-19 using Schrödinger suit. Molecules were selected from approved antiviral, anti-inflammatory or immunomodulatory classes. The viral proteins selected were angiotensin-converting enzyme 2 (ACE2), main protease (Mpro) and spike protein. Computational tools such as molecular docking, prime MM-GBSA, induced-fit docking (IFD) and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins.Results: The ligand-binding stability for the viral proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro) and 6M1D (ACE2), was in the order of Nintedanib>Quercetin, Nintedanib>Darunavir, Nintedanib> Baricitinib respectively. The MM-GBSA, IFD, and MD simulation studies infer that the drug nintedanib has the highest binding stability among the shortlisted molecules towards the selected viral target proteins. Conclusion: Nintedanib, which is primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing and used in the management of COVID-19.

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