Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout

2021 ◽  
Author(s):  
Peng Zhou ◽  
Heyi Wang ◽  
Zheng Chen ◽  
Qian Liu
Keyword(s):  
Essential Role ◽  
Therapeutic Strategy ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
S Protein ◽  
Peptide Specificity ◽  
Surface Receptor ◽  
Peptide Affinity ◽  
Indirect Readout ◽  
Intermolecular Recognition

Disrupting the intermolecular interaction of SARS-CoV-2 S protein with its cell surface receptor hACE2 is a therapeutic strategy against COVID-19. The protein context plays an essential role in hACE α1-helix recognition by viral S protein.

scholarly journals “Molecular Masks” for ACE2 to Effectively and Safely Block SARS-CoV-2 Virus Entry

2021 ◽  
Vol 22 (16) ◽  
pp. 8963
Author(s):  
Satya Prakash Shukla ◽  
Kwang Bog Cho ◽  
Vineeta Rustagi ◽  
Xiang Gao ◽  
Xinping Fu ◽  
...  
Keyword(s):  
Virus Entry ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Pressure Regulation ◽  
Converting Enzyme ◽  
Normal Blood Pressure ◽  
Health Crisis ◽  
Angiotensin Converting Enzyme 2 ◽  
Surface Receptor ◽  
Unique Cell

Coronavirus Disease 2019 (COVID-19) remains a global health crisis, despite the development and success of vaccines in certain countries. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, uses its spike protein to bind to the human cell surface receptor angiotensin-converting enzyme 2 (ACE2), which allows the virus to enter the human body. Using our unique cell screening technology, we identified two ACE2-binding peptoid compounds and developed dimeric derivatives (ACE2P1D1 and ACE2P2D1) that effectively blocked spike protein-ACE2 interaction, resulting in the inhibition of SARS-CoV-2 pseudovirus entry into human cells. ACE2P1D1 and ACE2P2D1 also blocked infection by a D614G mutant pseudovirus. More importantly, these compounds do not decrease ACE2 expression nor its enzyme activity (which is important in normal blood pressure regulation), suggesting safe applicability in humans

scholarly journals Extracellular vesicles containing ACE2 efficiently prevent infection by SARS-CoV-2 Spike protein-containing virus

2020 ◽  
Author(s):  
Federico Cocozza ◽  
Ester Piovesana ◽  
Nathalie Névo ◽  
Xavier Lahaye ◽  
Julian Buchrieser ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Extracellular Vesicles ◽  
Protein S ◽  
Spike Protein ◽  
S Protein ◽  
Surface Receptor

ABSTRACTSARS-CoV-2 entry is mediated by binding of the spike protein (S) to the surface receptor ACE2 and subsequent priming by TMPRRS2 allowing membrane fusion. Here, we produced extracellular vesicles (EVs) exposing ACE2 and demonstrate that ACE2-EVs are efficient decoys for SARS-CoV-2 S protein-containing lentivirus. Reduction of infectivity positively correlates with the level of ACE2, is 500 to 1500 times more efficient than with soluble ACE2 and further enhanced by the inclusion of TMPRSS2.

scholarly journals Hydroxyzine inhibits SARS-CoV-2 Spike protein binding to ACE2 in a qualitative in vitro assay

2021 ◽  
Author(s):  
Maria Dolores Rivas ◽  
Jose Maria Rafael Saponi-Cortes ◽  
Jose Zamorano
Keyword(s):  
Public Health Problem ◽  
In Vitro Assay ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Major Public Health Problem ◽  
Receptor Binding Domain ◽  
Vitro Assay ◽  
Surface Receptor

AbstractCOVID-19 currently represents a major public health problem. Multiple efforts are being performed to control this disease. Vaccinations are already in progress. However, no effective treatments have been found so far. The disease is caused by the SARS-CoV-2 coronavirus that through the Spike protein interacts with its cell surface receptor ACE2 to enter into the host cells. Therefore, compounds able to block this interaction may help to stop disease progression. In this study, we have analyzed the effect of compounds reported to interact and modify the activity of ACE2 on the binding of the Spike protein. Among the compounds tested, we found that hydroxyzine could inhibit the binding of the receptor-binding domain of Spike protein to ACE2 in a qualitative in vitro assay. This finding supports the reported clinical data showing the benefits of hydroxyzine on COVID-19 patients, raising the need for further investigation into its effectiveness in the treatment of COVID-19 given its well-characterized medical properties and affordable cost.

Inhibition of S-protein RBD and hACE2 Interaction for Control of SARSCoV-2 Infection (COVID-19)

2020 ◽  
Vol 20 ◽  
Author(s):  
Surendra Kumar Nayak
Keyword(s):  
Rna Virus ◽  
Cell Surface Receptor ◽  
Amino Acid Residues ◽  
Molecular Scaffolds ◽  
Early Screening ◽  
S Protein ◽  
Surface Receptor ◽  
Ic50 Values ◽  
Cellular Entry ◽  
Structural Aspects

Background: COVID-19 has become pandemic with higher morbidity and mortality rates after its start from Wuhan city of China. The infection by RNA virus, also known as SARS-CoV-2 or 2019-nCoV, from beta class of corona viruses has been found to be responsible for COVID-19. Structural analysis and evidences have been indicated that interaction between a segment of receptor binding domain (RBD) from S protein of virus and human angiotensin-converting enzyme 2 (hACE2) is essential for cellular entry of virus. Objective: The current review put the light on structural aspects for inhibition of RBD-hACE2 interaction mediated cellular entry of SARS-CoV-2. Methods: The present study provides a critical review of recently published information on RBD-hACE2 interaction and its inhibitors to control SARS-CoV-2 infection. The review highlighted the structural aspects of interaction between RBDhACE2 and involved amino acid residues. Results: Recently, several studies are being conducted for inhibition of the SARS-CoV-2 attachment and entry to the human cellular system. One of the important targets for viral invasion is its binding with cell surface receptor, hACE2, through RBD on S-protein. Mimicking of three residues on ACE2 (Lys31, Glu35 and Lys353 on B chain) provided hot target directed strategy for inhibition of early attachment of virus to the cell. Early screening of peptidic or non-peptidic molecules for inhibition of RBD-hACE2 interaction has been raised the hope for potential therapeutics against COVID-19. The higher affinity of molecules toward RBD than ACE2 is important factor for selectivity and minimization of ACE2 related adverse events on cardiovascular system, brain, kidney, and foetus development during pregnancy. Conclusion: Inhibition of RBD-hACE2 interaction by different molecular scaffolds can be used as a preferred strategy for control of SARS-CoV-2 infection. Recently, published reports pointed out Lys31, Glu35 and Lys353 on B chain of ACE2 as crucial residues for mimicking and design of novel molecules as inhibitors SARS-CoV-2 attachment to human cells. Moreover, some recently identified RBD-hACE2 interaction inhibitors have also been described with their protein binding pattern and potencies (IC50 values) which will help for further improvement in the selectivity.

SARS-CoV-2 Entry inhibitors targeting virus-ACE2 or virus-TMPRSS2 interactions

2021 ◽  
Vol 28 ◽  
Author(s):  
Hao Lin ◽  
Srinivasulu Cherukupalli ◽  
Da Feng ◽  
Shenghua Gao ◽  
Dongwei Kang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Entry Inhibitors ◽  
Concise Report ◽  
Surface Receptor ◽  
Transmembrane Serine Protease

: COVID-19 is an infectious disease caused by SARS-CoV-2. The life cycle of SARS-CoV-2 includes the entry into the target cells, replicase translation, replicating and transcribing genomes, translating structural proteins, assembling and releasing new virions. Entering host cells is a crucial stage in the early life cycle of the virus, and blocking this stage can effectively prevent virus infection. SARS enters the target cells mediated by the interaction between the viral S protein and the target cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the cleavage effect of type-II transmembrane serine protease (TMPRSS2) on the S protein. Therefore, the ACE2 receptor and TMPRSS2 are important targets for SARS-CoV-2 entry inhibitors. Herein, we provide a concise report/information on drugs with potential therapeutic value targeting virus-ACE2 or virus-TMPRSS2 interactions, to provide a reference for the design and discovery of potential entry inhibitors against SARS-CoV-2.

scholarly journals In Vitro Effect of Taraxacum officinale Leaf Aqueous Extract on the Interaction between ACE2 Cell Surface Receptor and SARS-CoV-2 Spike Protein D614 and Four Mutants

2021 ◽  
Vol 14 (10) ◽  
pp. 1055
Author(s):  
Hoai Thi Thu Tran ◽  
Michael Gigl ◽  
Nguyen Phan Khoi Le ◽  
Corinna Dawid ◽  
Evelyn Lamy
Keyword(s):  
Immune Escape ◽  
Taraxacum Officinale ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Post Exposure Prophylaxis ◽  
Lung Cells ◽  
Surface Receptor ◽  
Exposure Prophylaxis ◽  
Vitro Effect

To date, there have been rapidly spreading new SARS-CoV-2 “variants of concern”. They all contain multiple mutations in the ACE2 receptor recognition site of the spike protein, compared to the original Wuhan sequence, which is of great concern, because of their potential for immune escape. Here we report on the efficacy of common dandelion (Taraxacum officinale) to block protein–protein interaction of SARS-COV-2 spike to the human ACE2 receptor. This could be shown for the wild type and mutant forms (D614G, N501Y, and a mix of K417N, E484K, and N501Y) in human HEK293-hACE2 kidney and A549-hACE2-TMPRSS2 lung cells. High-molecular-weight compounds in the water-based extract account for this effect. Infection of the lung cells using SARS-CoV-2 spike D614 and spike Delta (B.1.617.2) variant pseudotyped lentivirus particles was efficiently prevented by the extract and so was virus-triggered pro-inflammatory interleukin 6 secretion. Modern herbal monographs consider the usage of this medicinal plant as safe. Thus, the in vitro results reported here should encourage further research on the clinical relevance and applicability of the extract as prevention strategy for SARS-CoV-2 infection in terms of a non-invasive, oral post-exposure prophylaxis.

scholarly journals COVID-19: Probing the Possibility of Transmission in Animal Kingdom

2020 ◽  
Author(s):  
Tawsif Ahmed Kazi ◽  
Suranjita Mitra ◽  
Bidhan Chandra Mukhopadhyay ◽  
Rajarshi Bhattacharya ◽  
Sukhendu Mandal ◽  
...  
Keyword(s):  
Global Economy ◽  
Comparative Sequence Analysis ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Broad Host Range ◽  
The Public ◽  
Molecular Events ◽  
Surface Receptor ◽  
Rats And Mice ◽  
Aquatic Mammals

The recent 2019-nCoV outbreak, spreading infection around the globe is jeopardizing the public health and global economy. The virus was reported to have emerged from an animal market in Wuhan, China at the end of 2019 and presumed to have originated from bats and eventually transmitted in humans. The entry of the virus into human cells is triggered by a series of molecular events initiated with the binding of a receptor-binding domain of viral spike protein to human Ace2 cell surface receptor. Based on the comparative sequence analysis of the well-known binding hotspots of human Ace2, cross-interacting potential of 2019-nCoV was predicted, which suggests Ace2 of wild animals like tiger, bear, orangutan, etc.; aquatic mammals like whale and dolphins; and domestic animals like cat, horse, goat, sheep, dog etc. as potential target. However, the recognition of Ace2 of bats, rats and mice by the 2019-nCoV spike protein remains under question. The study indicates that 2019-nCoV might have broad host range and may thus intensify the gravity of 2019-nCoV outbreak

scholarly journals Virtual Screening of Phytochemical Compounds as Potential Inhibitors against SARS-CoV-2 Infection

2020 ◽  
Author(s):  
Ram Kothandan ◽  
Cashlin Anna Suveetha Gnana Rajan ◽  
Janamitra Arjun ◽  
Rejoe Raymond Michael Raj ◽  
Sowfia Syed
Keyword(s):  
Hydrophobic Interaction ◽  
Interaction Analysis ◽  
Respiratory Illness ◽  
Docking Studies ◽  
Cell Surface Receptor ◽  
Retroviral Infection ◽  
S Protein ◽  
Surface Receptor ◽  
Phytochemical Compounds ◽  
Potential Inhibitors

Abstract Background: The present pandemic situation due to coronavirus has led to the search for newer prevention, diagnostic and treatment methods. The onset of the corona infection in a human results in acute respiratory illness followed by death if not diagnosed and treated with suitable anti-retroviral drugs. With the unavailability of the targeted drug treatment, several repurposed drugs are being used for treatment, However, the side-effects of the drugs urges us to move to a search for newer synthetic or phytochemical based drugs. The present study investigates the use of various phytochemicals virtually screened from various plant sources in Western Ghats, India and subsequently molecular docking studies were performed to identify the efficacy of the drug in retroviral infection particularly coronavirus infection.Results: Out of 57 phytochemical screened initially based on the structural and physicochemical properties, 39 were effectively used for the docking analysis. Finally 5 lead compound with highest hydrophobic interaction and number of H-bonds were screened. Results from the interaction analysis suggests, Piperolactam A to be pocketed well with good hydrophobic interaction with the residues in the binding region R1. ADME and toxicity profiling also reveals Piperolactam A with higher LogS vlaues indicating higher permeation and hydrophilicity. Toxicity profiling suggests that the 5 screened compounds to be relatively safe.Conclusion: The insilico methods used in this study suggests that the compound Piperolactum A to be the most effective inhibitor of S-protein from binding to the GRP78 receptor. By blocking the binding of the S-protein to the CS-GRP78 cell surface receptor, they can inhibit the binding of the virus to the host.

scholarly journals N and O glycosylation of the SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Miloslav Sanda ◽  
Lindsay Morrison ◽  
Radoslav Goldman
Keyword(s):  
Current Knowledge ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
World Health ◽  
Furin Cleavage ◽  
Proteolytic Activation ◽  
Health Crisis ◽  
Antiviral Compounds ◽  
Furin Cleavage Site ◽  
Surface Receptor

ABSTRACTCovid-19 pandemic outbreak is the reason of the current world health crisis. The development of effective antiviral compounds and vaccines requires detailed descriptive studies of the SARS-CoV-2 proteins. The SARS-CoV-2 spike (S) protein mediates virion binding to the human cells through its interaction with the ACE2 cell surface receptor and is one of the prime immunization targets. A functional virion is composed of three S1 and three S2 subunits created by furin cleavage of the spike protein at R682, a polybasic cleavage sites that differs from the SARS-CoV spike protein of 2002. We observe that the spike protein is O-glycosylated on a threonine (T678) near the furin cleavage site occupied by core-1 and core-2 structures. In addition, we have identified eight additional O-glycopeptides on the spike glycoprotein and we confirmed that the spike protein is heavily N-glycosylated. Our recently developed LC-MS/MS methodology allowed us to identify LacdiNAc structural motives on all occupied N-glycopeptides and polyLacNAc structures on six glycopeptides of the spike protein. In conclusion, our study substantially expands the current knowledge of the spike protein’s glycosylation and enables the investigation of the influence of the O-glycosylation on its proteolytic activation.

scholarly journals Virtual screening of phytochemical compounds as potential inhibitors against SARS-CoV-2 infection

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Ram Kothandan ◽  
Cashlin Anna Suveetha Gnana Rajan ◽  
Janamitra Arjun ◽  
Rejoe Raymond Michael Raj ◽  
Sowfia Syed
Keyword(s):  
Hydrophobic Interaction ◽  
Interaction Analysis ◽  
Respiratory Illness ◽  
Docking Studies ◽  
Antiretroviral Drugs ◽  
Cell Surface Receptor ◽  
Retroviral Infection ◽  
S Protein ◽  
Surface Receptor ◽  
Potential Inhibitors

Abstract Background The present pandemic situation due to coronavirus has led to the search for newer prevention, diagnostic, and treatment methods. The onset of the corona infection in a human results in acute respiratory illness followed by death if not diagnosed and treated with suitable antiretroviral drugs. With the unavailability of the targeted drug treatment, several repurposed drugs are being used for treatment. However, the side-effects of the drugs urges us to move to a search for newer synthetic- or phytochemical-based drugs. The present study investigates the use of various phytochemicals virtually screened from various plant sources in Western Ghats, India, and subsequently molecular docking studies were performed to identify the efficacy of the drug in retroviral infection particularly coronavirus infection. Results Out of 57 phytochemicals screened initially based on the structural and physicochemical properties, 39 were effectively used for the docking analysis. Finally, 5 lead compounds with highest hydrophobic interaction and number of H-bonds were screened. Results from the interaction analysis suggest Piperolactam A to be pocketed well with good hydrophobic interaction with the residues in the binding region R1. ADME and toxicity profiling also reveals Piperolactam A with higher LogS values indicating higher permeation and hydrophilicity. Toxicity profiling suggests that the 5 screened compounds to be relatively safe. Conclusion The in silico methods used in this study suggests that the compound Piperolactam A to be the most effective inhibitor of S-protein from binding to the GRP78 receptor. By blocking the binding of the S-protein to the CS-GRP78 cell surface receptor, they can inhibit the binding of the virus to the host.

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