scholarly journals Interactions of SARS-CoV-2 envelope protein with amilorides correlate with antiviral activity

2021 ◽  
Author(s):  
Sang Ho Park ◽  
Haley Siddiqi ◽  
Daniela V. Castro ◽  
Anna De Angelis ◽  
Aaron L. Oom ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Chemical Shift ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Binding Site ◽  
Transmembrane Domain ◽  
The Novel ◽  
Structure And Dynamics ◽  
E Protein ◽  
Novel Coronavirus

AbstractSARS-CoV-2 is the novel coronavirus that is the causative agent of COVID-19, a sometimes-lethal respiratory infection responsible for a world-wide pandemic. The envelope (E) protein, one of four structural proteins encoded in the viral genome, is a 75-residue integral membrane protein whose transmembrane domain exhibits ion channel activity and whose cytoplasmic domain participates in protein-protein interactions. These activities contribute to several aspects of the viral replication-cycle, including virion assembly, budding, release, and pathogenesis. Here, we describe the structure and dynamics of full-length SARS-CoV-2 E protein in hexadecylphosphocholine micelles by NMR spectroscopy. We also characterized its interactions with four putative ion channel inhibitors. The chemical shift index and dipolar wave plots establish that E protein consists of a long transmembrane helix (residues 8-43) and a short cytoplasmic helix (residues 53-60) connected by a complex linker that exhibits some internal mobility. The conformations of the N-terminal transmembrane domain and the C-terminal cytoplasmic domain are unaffected by truncation from the intact protein. The chemical shift perturbations of E protein spectra induced by the addition of the inhibitors demonstrate that the N-terminal region (residues 6-18) is the principal binding site. The binding affinity of the inhibitors to E protein in micelles correlates with their antiviral potency in Vero E6 cells: HMA ≈ EIPA > DMA >> Amiloride, suggesting that bulky hydrophobic groups in the 5’ position of the amiloride pyrazine ring play essential roles in binding to E protein and in antiviral activity. An N15A mutation increased the production of virus-like particles, induced significant chemical shift changes from residues in the inhibitor binding site, and abolished HMA binding, suggesting that Asn15 plays a key role in maintaining the protein conformation near the binding site. These studies provide the foundation for complete structure determination of E protein and for structure-based drug discovery targeting this protein.Author SummaryThe novel coronavirus SARS-CoV-2, the causative agent of the world-wide pandemic of COVID-19, has become one of the greatest threats to human health. While rapid progress has been made in the development of vaccines, drug discovery has lagged, partly due to the lack of atomic-resolution structures of the free and drug-bound forms of the viral proteins. The SARS-CoV-2 envelope (E) protein, with its multiple activities that contribute to viral replication, is widely regarded as a potential target for COVID-19 treatment. As structural information is essential for drug discovery, we established an efficient sample preparation system for biochemical and structural studies of intact full-length SARS-CoV-2 E protein and characterized its structure and dynamics. We also characterized the interactions of amilorides with specific E protein residues and correlated this with their antiviral activity during viral replication. The binding affinity of the amilorides to E protein correlated with their antiviral potency, suggesting that E protein is indeed the likely target of their antiviral activity. We found that residue asparagine15 plays an important role in maintaining the conformation of the amiloride binding site, providing molecular guidance for the design of inhibitors targeting E protein.

scholarly journals Interactions of SARS-CoV-2 envelope protein with amilorides correlate with antiviral activity

2021 ◽  
Vol 17 (5) ◽  
pp. e1009519
Author(s):  
Sang Ho Park ◽  
Haley Siddiqi ◽  
Daniela V. Castro ◽  
Anna A. De Angelis ◽  
Aaron L. Oom ◽  
...  
Keyword(s):  
Chemical Shift ◽  
Antiviral Activity ◽  
Ion Channel ◽  
Binding Site ◽  
Protein Interactions ◽  
Transmembrane Domain ◽  
Cytoplasmic Domain ◽  
Intact Protein ◽  
Chemical Shift Index ◽  
E Protein

SARS-CoV-2 is the novel coronavirus that is the causative agent of COVID-19, a sometimes-lethal respiratory infection responsible for a world-wide pandemic. The envelope (E) protein, one of four structural proteins encoded in the viral genome, is a 75-residue integral membrane protein whose transmembrane domain exhibits ion channel activity and whose cytoplasmic domain participates in protein-protein interactions. These activities contribute to several aspects of the viral replication-cycle, including virion assembly, budding, release, and pathogenesis. Here, we describe the structure and dynamics of full-length SARS-CoV-2 E protein in hexadecylphosphocholine micelles by NMR spectroscopy. We also characterized its interactions with four putative ion channel inhibitors. The chemical shift index and dipolar wave plots establish that E protein consists of a long transmembrane helix (residues 8–43) and a short cytoplasmic helix (residues 53–60) connected by a complex linker that exhibits some internal mobility. The conformations of the N-terminal transmembrane domain and the C-terminal cytoplasmic domain are unaffected by truncation from the intact protein. The chemical shift perturbations of E protein spectra induced by the addition of the inhibitors demonstrate that the N-terminal region (residues 6–18) is the principal binding site. The binding affinity of the inhibitors to E protein in micelles correlates with their antiviral potency in Vero E6 cells: HMA ≈ EIPA > DMA >> Amiloride, suggesting that bulky hydrophobic groups in the 5’ position of the amiloride pyrazine ring play essential roles in binding to E protein and in antiviral activity. An N15A mutation increased the production of virus-like particles, induced significant chemical shift changes from residues in the inhibitor binding site, and abolished HMA binding, suggesting that Asn15 plays a key role in maintaining the protein conformation near the binding site. These studies provide the foundation for complete structure determination of E protein and for structure-based drug discovery targeting this protein.

scholarly journals Microbes, Clinical trials, Drug Discovery, and Vaccine Development: The Current Perspectives

2021 ◽  
Vol 4 (4) ◽  
pp. 311-323
Author(s):  
Venkataramana Kandi ◽  
Tarun Kumar Suvvari ◽  
Sabitha Vadakedath ◽  
Vikram Godishala
Keyword(s):  
Drug Discovery ◽  
Genetic Variants ◽  
Vaccine Development ◽  
Treatment Options ◽  
Morbidity And Mortality ◽  
Therapeutic Interventions ◽  
Multi Drug Resistance ◽  
The Novel ◽  
Normal Human ◽  
Novel Coronavirus

Because of the frequent emergence of novel microbial species and the re-emergence of genetic variants of hitherto known microbes, the global healthcare system, and human health has been thrown into jeopardy. Also, certain microbes that possess the ability to develop multi-drug resistance (MDR) have limited the treatment options in cases of serious infections, and increased hospital and treatment costs, and associated morbidity and mortality. The recent discovery of the novel Coronavirus (n-CoV), the Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2) that is causing the CoV Disease-19 (COVID-19) has resulted in severe morbidity and mortality throughout the world affecting normal human lives. The major concern with the current pandemic is the non-availability of specific drugs and an incomplete understanding of the pathobiology of the virus. It is therefore important for pharmaceutical establishments to envisage the discovery of therapeutic interventions and potential vaccines against the novel and MDR microbes. Therefore, this review is attempted to update and explore the current perspectives in microbes, clinical research, drug discovery, and vaccine development to effectively combat the emerging novel and re-emerging genetic variants of microbes.

Use of Artificial Intelligence (AI) in Fighting With the Novel Coronavirus (COVID-19)

2021 ◽  
pp. 21-30
Author(s):  
Anuja Rajendra Jadhav ◽  
Roshani Raut ◽  
Ram Joshi ◽  
Pranav D. Pathak ◽  
Anuja R. Zade
Keyword(s):  
Artificial Intelligence ◽  
Drug Discovery ◽  
Active Learning ◽  
The Novel ◽  
Response Recovery ◽  
Control And Prevention ◽  
Virus Attack ◽  
Detection Response ◽  
Novel Coronavirus

2020 started with the outbreak of the novel coronavirus (COVID-19) virus. In this panic situation, the combination of artificial intelligence (AI) can help us in fight against the deadliest virus attack worldwide. This tool can be used to control and prevention of the outbreak disease. The AI tool can be helpful in prediction, detection, response, recovery, drug discovery of the disease. The AI-driven tools can be used in identifying the nature of outbreak as well as in forecasting the spread and coverage worldwide. In this case, so many AI-based tools can be applied and trained using active learning-based models for the detection, prevention, treatment, and recovery of the patients. Also, they can help us for identifying infected persons from the non-infected to stop the spread of the virus. This chapter mainly focuses on the AI-assisted methodology and models that can help in fighting COVID-19.

scholarly journals Lithium and coronaviral infections. A scoping review.

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 93 ◽  
Author(s):  
Jan K. Nowak ◽  
Jarosław Walkowiak
Keyword(s):  
Bipolar Disorder ◽  
Antiviral Activity ◽  
Scoping Review ◽  
Systematic Approach ◽  
Research Community ◽  
The Novel ◽  
Mechanistic Investigation ◽  
Rapid Spread ◽  
Novel Coronavirus

The current rapid spread of the novel coronavirus (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) calls for a rapid response from the research community. Lithium is widely used to treat bipolar disorder, but has been shown to exhibit antiviral activity. This brief review took a systematic approach to identify six in vitro studies reporting on the influence of lithium on coronaviral infections. We propose mechanistic investigation of the influence of lithium – alone and with chloroquine – on the SARS-CoV-2 infection.

scholarly journals Targeted Drug Repurposing Against the SARS-CoV-2 E channel Identifies Blockers With in vitro Antiviral Activity

2021 ◽  
Author(s):  
Prabhat Pratap Singh Tomar ◽  
Miriam Krugliak ◽  
Isaiah Tuvia Arkin
Keyword(s):  
Tissue Culture ◽  
Ion Channels ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Drug Repurposing ◽  
Viral Spread ◽  
E Protein ◽  
Human Use ◽  
The Impact

It is difficult to overstate the impact that COVID-19 had on humankind. The pandemic’s etiological agent, SARS-CoV-2, is a member of the Coronaviridae, and as such, is an enveloped virus with ion channels in its membrane. Therefore, in an attempt to provide an option to curb the viral spread, we searched for blockers of its E protein viro-porin. Using three bacteria-based assays, we identified eight compounds that exhibited activity after screening a library of ca. 3000 approved-for-human-use drugs. Reassuringly, analysis of viral replication in tissue culture indicated that most of the compounds could reduce infectivity to varying extents. In conclusion, targeting a particular channel in the virus for drug repurposing may increase our arsenal of treatment options to combat COVID-19 virulence.Significance StatementThe goal of our study was to expand the treatment arsenal against COVID-19. To that end, we have decided to focus on drug therapy, and as a target - the E protein, an ion channel in the virus. Ion channels as a family are excellent drug targets, but viral channels have been underexploited for pharmaceutical point intervention. To hasten future regulatory requirements and focus the chemical search space, we screened a library of ca. 3000 approved-for-human-use drugs using three independent bacteria-based assays. Our results yielded eight compounds, which were subsequently tested for antiviral activity in tissue culture. Gratifyingly, most compounds were able to reduce viral replication, and as such, both validate our approach and potentially augment our anti-COVID tool kit.

scholarly journals Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245013
Author(s):  
Sixue Zhang ◽  
Atefeh Garzan ◽  
Nicole Haese ◽  
Robert Bostwick ◽  
Yohanka Martinez-Gzegozewska ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Carboxylic Acid ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Chikungunya Virus ◽  
X Ray ◽  
X Ray Crystallography ◽  
Small Molecule Drugs ◽  
Fragment Library ◽  
Fragment Based Drug Discovery

The macrodomain of nsP3 (nsP3MD) is highly conserved among the alphaviruses and ADP-ribosylhydrolase activity of Chikungunya Virus (CHIKV) nsP3MD is critical for CHIKV viral replication and virulence. No small molecule drugs targeting CHIKV nsP3 have been identified to date. Here we report small fragments that bind to nsP3MD which were discovered by virtually screening a fragment library and X-ray crystallography. These identified fragments share a similar scaffold, 2-pyrimidone-4-carboxylic acid, and are specifically bound to the ADP-ribose binding site of nsP3MD. Among the fragments, 2-oxo-5,6-benzopyrimidine-4-carboxylic acid showed anti-CHIKV activity with an IC50 of 23 μM. Our fragment-based drug discovery approach provides valuable information to further develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on the 2-pyrimidone-4-carboxylic acid scaffold. In silico studies suggest this pyrimidone scaffold could also bind to the macrodomains of other alphaviruses and coronaviruses and thus, have potential pan-antiviral activity.

scholarly journals HTCC as a highly effective polymeric inhibitor of SARS-CoV-2 and MERS-CoV

2020 ◽  
Author(s):  
Aleksandra Milewska ◽  
Ying Chi ◽  
Artur Szczepanski ◽  
Emilia Barreto-Duran ◽  
Kevin Liu ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
The Novel ◽  
Highly Pathogenic ◽  
Global Crisis ◽  
Potential Inhibitor ◽  
Highly Effective ◽  
Novel Coronavirus ◽  
Global And Local

ABSTRACTThe beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the healthcare measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of previously developed by us HTCC compound (N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride), which may be used as potential inhibitor of currently circulating highly pathogenic coronaviruses – SARS-CoV-2 and MERS-CoV.

scholarly journals Immunoboosting Potential of Spices with Special Reference to North East India against the Novel Coronavirus Pandemic- A Review

2021 ◽  
pp. 207-218
Author(s):  
Rahul Malakar ◽  
Amrit Kumar ◽  
Priyanka Das ◽  
Khusbu Pathak ◽  
Rajesh Dev Sarkar
Keyword(s):  
Immune System ◽  
Antiviral Activity ◽  
Special Reference ◽  
The Novel ◽  
Protective Activity ◽  
North East India ◽  
North East ◽  
Household Products ◽  
Health Promoting ◽  
Novel Coronavirus

Spices, which is key ingredient in every household products not only used for adding aroma to food but however, has health promoting and protective activity against foreign pathogens. Different spices used in day to day life boosts the immune system that leads to healthy and prosperous life. The commonly used spices not only have antimicrobial or antiviral activity, but also serve as a rich source of various vitamins, minerals, antioxidants etc. The medicinal importance of spices dates from ancient Ayurveda and many studies indicating the potential of spices as immunoboosting agent had been carried out in the recent years. Therefore, this review highlights the medicinal importance of commonly used spices in North-East India as immunobooster against the current coronavirus pandemic.

scholarly journals Cryo-EM as a powerful tool for drug discovery: recent structural based studies of SARS-CoV-2

2021 ◽  
Vol 51 (1) ◽  
Author(s):  
Han-ul Kim ◽  
Hyun Suk Jung
Keyword(s):  
Drug Discovery ◽  
Large Scale ◽  
Therapeutic Agent ◽  
The Novel ◽  
Structure Based Drug Design ◽  
Binding Reaction ◽  
Drug Candidates ◽  
Cryo Electron Microscopy ◽  
Global Pandemic ◽  
Novel Coronavirus

AbstractThe novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has arisen as a global pandemic affecting the respiratory system showing acute respiratory distress syndrome (ARDS). However, there is no targeted therapeutic agent yet and due to the growing cases of infections and the rising death tolls, discovery of the possible drug is the need of the hour. In general, the study for discovering therapeutic agent for SARS-CoV-2 is largely focused on large-scale screening with fragment-based drug discovery (FBDD). With the recent advancement in cryo-electron microscopy (Cryo-EM), it has become one of the widely used tools in structural biology. It is effective in investigating the structure of numerous proteins in high-resolution and also had an intense influence on drug discovery, determining the binding reaction and regulation of known drugs as well as leading the design and development of new drug candidates. Here, we review the application of cryo-EM in a structure-based drug design (SBDD) and in silico screening of the recently acquired FBDD in SARS-CoV-2. Such insights will help deliver better understanding in the procurement of the effective remedial solution for this pandemic.

scholarly journals Structure and dynamics of the SARS-CoV-2 envelope protein monomer

2021 ◽  
Author(s):  
Alexander Kuzmin ◽  
Philipp Orekhov ◽  
Roman Astashkin ◽  
Valentin Gordeliy ◽  
Ivan Gushchin
Keyword(s):  
Envelope Protein ◽  
Transmembrane Domain ◽  
Membrane Surface ◽  
Protein A ◽  
Membrane Curvature ◽  
Curvature Sensing ◽  
Structure And Dynamics ◽  
E Protein ◽  
Viral Particles ◽  
Dynamics Simulations

AbstractCoronaviruses, especially SARS-CoV-2, present an ongoing threat for human wellbeing. Consequently, elucidation of molecular determinants of their function and interaction with host is an important task. Whereas some of the coronaviral proteins are extensively characterized, others remain understudied. Here, we use molecular dynamics simulations to analyze the structure and dynamics of the SARS-CoV-2 envelope protein (E protein, a viroporin) in the monomeric form. The protein consists of three parts: hydrophobic α-helical transmembrane domain (TMD) and amphiphilic α-helices H2 and H3, which are connected by flexible linkers. We show that TMD is tilted in the membrane, with phenylalanines Phe20, Phe23 and Phe26 facing the lumen. H2 and H3 reside at the membrane surface. Orientation of H2 is not affected by glycosylation, but strongly influenced by palmitoylation pattern of cysteines Cys40, Cys43 and Cys44. On the other hand, glycosylation affects the orientation of H3 and prevents its stacking with H2. We also find that the E protein both generates and senses the membrane curvature, preferably localizing with the cytoplasmic part at the convex regions of the membrane. Curvature sensing may be favorable for assembly of the E protein oligomers, whereas induction of curvature may facilitate budding of the viral particles. The presented results may be helpful for better understanding of the function of coronaviral E protein and viroporins in general, and for overcoming the ongoing SARS-CoV-2 pandemic.

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