scholarly journals Molecular Mechanism of Evolution and Human Infection with SARS-CoV-2

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 428 ◽  
Author(s):  
Jiahua He ◽  
Huanyu Tao ◽  
Yumeng Yan ◽  
Sheng-You Huang ◽  
Yi Xiao
Keyword(s):  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Md Simulations ◽  
Protein Docking ◽  
Human Infection ◽  
Spike Protein ◽  
Temperature Sensitive ◽  
Health Crisis ◽  
Novel Coronavirus ◽  
Respiratory Coronavirus

The outbreak of a novel coronavirus, which was later formally named the severe acute respiratory coronavirus 2 (SARS-CoV-2), has caused a worldwide public health crisis. Previous studies showed that SARS-CoV-2 is highly homologous to SARS-CoV and infects humans through the binding of the spike protein to ACE2. Here, we have systematically studied the molecular mechanisms of human infection with SARS-CoV-2 and SARS-CoV by protein-protein docking and MD simulations. It was found that SARS-CoV-2 binds ACE2 with a higher affinity than SARS-CoV, which may partly explain that SARS-CoV-2 is much more infectious than SARS-CoV. In addition, the spike protein of SARS-CoV-2 has a significantly lower free energy than that of SARS-CoV, suggesting that SARS-CoV-2 is more stable and may survive a higher temperature than SARS-CoV. This provides insights into the evolution of SARS-CoV-2 because SARS-like coronaviruses have originated in bats. Our computation also suggested that the RBD-ACE2 binding for SARS-CoV-2 is much more temperature-sensitive than that for SARS-CoV. Thus, it is expected that SARS-CoV-2 would decrease its infection ability much faster than SARS-CoV when the temperature rises. These findings would be beneficial for the disease prevention and drug/vaccine development of SARS-CoV-2.

scholarly journals Molecular mechanism of evolution and human infection with the novel coronavirus (2019-nCoV)

2020 ◽  
Author(s):  
Jiahua He ◽  
Huanyu Tao ◽  
Yumeng Yan ◽  
Sheng-You Huang ◽  
Yi Xiao
Keyword(s):  
Free Energy ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Binding Free Energy ◽  
Protein Docking ◽  
Human Infection ◽  
Host Cells ◽  
Spike Protein ◽  
Temperature Sensitive ◽  
Health Crisis

AbstractSince December, 2019, an outbreak of pneumonia caused by the new coronavirus (2019-nCoV) has hit the city of Wuhan in the Hubei Province. With the continuous development of the epidemic, it has become a national public health crisis and calls for urgent antiviral treatments or vaccines. The spike protein on the coronavirus envelope is critical for host cell infection and virus vitality. Previous studies showed that 2019-nCoV is highly homologous to human SARS-CoV and attaches host cells though the binding of the spike receptor binding domain (RBD) domain to the angiotensin-converting enzyme II (ACE2). However, the molecular mechanisms of 2019-nCoV binding to human ACE2 and evolution of 2019-nCoV remain unclear. In this study, we have extensively studied the RBD-ACE2 complex, spike protein, and free RBD systems of 2019-nCoV and SARS-CoV using protein-protein docking and molecular dynamics (MD) simulations. It was shown that the RBD-ACE2 binding free energy for 2019-nCoV is significantly lower than that for SARS-CoV, which is consistent with the fact that 2019-nCoV is much more infectious than SARS-CoV. In addition, the spike protein of 2019-nCoV shows a significantly lower free energy than that of SARS-CoV, suggesting that 2019-nCoV is more stable and able to survive a higher temperature than SARS-CoV. This may also provide insights into the evolution of 2019-nCoV because SARS-like coronaviruses are thought to have originated in bats that are known to have a higher body-temperature than humans. It was also revealed that the RBD of 2019-nCoV is much more flexible especially near the binding site and thus will have a higher entropy penalty upon binding ACE2, compared to the RBD of SARS-CoV. That means that 2019-nCoV will be much more temperature-sensitive in terms of human infection than SARS-CoV. With the rising temperature, 2019-nCoV is expected to decrease its infection ability much faster than SARS-CoV, and get controlled more easily. The present findings are expected to be helpful for the disease prevention and control as well as drug and vaccine development of 2019-nCoV.

scholarly journals DockCoV2: a drug database against SARS-CoV-2

2020 ◽  
Vol 49 (D1) ◽  
pp. D1152-D1159 ◽  
Author(s):  
Ting-Fu Chen ◽  
Yu-Chuan Chang ◽  
Yi Hsiao ◽  
Ko-Han Lee ◽  
Yu-Chun Hsiao ◽  
...  
Keyword(s):  
Viral Entry ◽  
Experimental Information ◽  
Protein Docking ◽  
Spike Protein ◽  
Health Crisis ◽  
N Protein ◽  
Drug Database ◽  
Serine Protease Family ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

Abstract The current state of the COVID-19 pandemic is a global health crisis. To fight the novel coronavirus, one of the best-known ways is to block enzymes essential for virus replication. Currently, we know that the SARS-CoV-2 virus encodes about 29 proteins such as spike protein, 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), Papain-like protease (PLpro), and nucleocapsid (N) protein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) for viral entry and transmembrane serine protease family member II (TMPRSS2) for spike protein priming. Thus in order to speed up the discovery of potential drugs, we develop DockCoV2, a drug database for SARS-CoV-2. DockCoV2 focuses on predicting the binding affinity of FDA-approved and Taiwan National Health Insurance (NHI) drugs with the seven proteins mentioned above. This database contains a total of 3,109 drugs. DockCoV2 is easy to use and search against, is well cross-linked to external databases, and provides the state-of-the-art prediction results in one site. Users can download their drug-protein docking data of interest and examine additional drug-related information on DockCoV2. Furthermore, DockCoV2 provides experimental information to help users understand which drugs have already been reported to be effective against MERS or SARS-CoV. DockCoV2 is available at https://covirus.cc/drugs/.

scholarly journals Apigetrin inhibits cytotoxicity and dysregulation of ACE2, IL1α and TGFβ expression induced by recombinant spike protein of SARS-CoV-2

2021 ◽  
Vol 9 (2) ◽  
pp. 144-154
Author(s):  
Grace Luo ◽  
Wei Zhu
Keyword(s):  
Cell Proliferation ◽  
Cytotoxic Effect ◽  
Molecular Mechanisms ◽  
Cell Injury ◽  
Cytokine Production ◽  
Human Cells ◽  
Spike Protein ◽  
Dependent Manner ◽  
Pathological Effect ◽  
Health Crisis

SARS-CoV-2 virus is a novel coronavirus that was first identified in Wuhan, China in December 2019 and has caused an ongoing global health crisis. It has been a worldwide focus in research to understand viral pathogenesis and discover effective therapies. SARS-CoV-2 belongs to the same genus as the viruses responsible for Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS). Spike protein (SP) on SARS-CoV-2 plays a key role in the pathogenesis of SARS-CoV-2. The virus enters human cells via the binding of SP to the angiotensin-converting enzyme 2 (ACE2) on human cells. The binding of SP inhibits ACE2 function by reducing formation of angiotensin-(1-7), a compound that has inhibitory effects on inflammation. In addition, SARS-CoV-2 induces excessive proinflammatory cytokine production through various other signaling pathways such as the NFκB and NLRP3 inflammasome pathways. Previous evidence showed that apigenin (APG), a plant phenolic compound, can bind to SP. However, whether or not apigetrin (APT), the glucoside conjugate of APG, can protect human cells against cell injury caused by SARS-CoV-2 is still unknown. Studies have shown that SARS-CoV-2 induced dysregulation of host cell ACE2 expression is one of the major pathophysiological factors of COVID-19 infection. Our current study demonstrated that recombinant SP significantly reduced ACE2 level in human neuronal cells in a dose dependent manner using ELISA assay. Interestingly, APT reversed the SP induced ACE2 downregulation in these cells. In this study, the effect of SP on cell proliferation and immune regulation was also investigated. Using MTT and LDH assays, I discovered that SP had a cytotoxic effect on these cells and significantly inhibited cell proliferation. This cytotoxic effect was mitigated by adding APT treatment. Furthermore, APT reduced SP induced cytokine production such as IL1α and TGFβ . In sum, my study demonstrated that APT inhibited SARS-CoV-2 SP induced dysregulation of human cells and reduced its cytotoxic effects on cells. APT significantly upregulated ACE2 expression and inhibited the production of cytokines IL1α and TGFβ in the cells treated with SP. My study indicated that APT has potential to be a novel therapy for COVID-19 infection. More experiments to further elucidate molecular mechanisms of how APT modulates pathological effect of SP with different in vitro models including other human cell lines and in vivo animal models are currently being performed.

scholarly journals Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Cecylia S. Lupala ◽  
Xuanxuan Li ◽  
Jian Lei ◽  
Hong Chen ◽  
Jianxun Qi ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Genomic Analysis ◽  
Md Simulations ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Binding Modes ◽  
Angiotensin Converting Enzyme 2 ◽  
Causal Pathogen ◽  
Novel Coronavirus

AbstractA novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 pneumonia, an outbreak started near the end of 2019 in Wuhan, China. The SARS-CoV-2 was found to be closely related to the SARS-CoV, based on the genomic analysis. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2 as well, initiated by the binding of the spike protein to the human ACE2. Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The predicted model is highly consistent with the experimentally determined complex structures. Plausible binding modes between human ACE2 and the RBD were revealed from all-atom MD simulations. The simulation data further revealed critical residues at the complex interface and provided more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Two mutants mimicking rat ACE2 were modeled to study the mutation effects on RBD binding to ACE2. The simulations showed that the N-terminal helix and the K353 of the human ACE2 alter the binding modes of the CoV2-RBD to the ACE2.

scholarly journals Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein

2020 ◽  
Vol 73 (7) ◽  
pp. 366-369 ◽  
Author(s):  
Tahir S Pillay
Keyword(s):  
Receptor Binding ◽  
Transmembrane Domain ◽  
Vaccine Development ◽  
Protein S ◽  
Respiratory Illness ◽  
Spike Protein ◽  
Furin Cleavage ◽  
Furin Cleavage Site ◽  
Cellular Entry ◽  
Novel Coronavirus

The year 2020 has seen a major and sustained outbreak of a novel betacoronavirus (severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2) infection that causes fever, severe respiratory illness and pneumonia, a disease called COVID-19. At the time of writing, the death toll was greater than 120 000 worldwide with more than 2 million documented infections. The genome of the CoV encodes a number of structural proteins that facilitate cellular entry and assembly of virions, of which the spike protein S appears to be critical for cellular entry. The spike protein guides the virus to attach to the host cell. The spike protein contains a receptor-binding domain (RBD), a fusion domain and a transmembrane domain. The RBD of spike protein S binds to Angiotensin Converting Enzyme 2 (ACE2) to initiate cellular entry. The spike protein of SARS-CoV-2 shows more than 90% amino acid similarity to the pangolin and bat CoVs and these also use ACE2 as a receptor. Binding of the spike protein to ACE2 exposes the cleavage sites to cellular proteases. Cleavage of the spike protein by transmembrane protease serine 2 and other cellular proteases initiates fusion and endocytosis. The spike protein contains an addition furin cleavage site that may allow it to be ‘preactivated’ and highly infectious after replication. The fundamental role of the spike protein in infectivity suggests that it is an important target for vaccine development, blocking therapy with antibodies and diagnostic antigen-based tests. This review briefly outlines the structure and function of the 2019 novel CoV/SARS-CoV-2 spike protein S.

scholarly journals COVID-19 and Extracellular Vesicles: An Intriguing Interplay

2020 ◽  
Vol 45 (5) ◽  
pp. 661-670
Author(s):  
Gabriella Pocsfalvi ◽  
Ramila Mammadova ◽  
Ana Paulina Ramos Juarez ◽  
Ramesh Bokka ◽  
Francesco Trepiccione ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Viral Entry ◽  
Viral Infections ◽  
Vaccine Development ◽  
Antiviral Drug ◽  
The Novel ◽  
Health Crisis ◽  
Cargo Delivery ◽  
The Many ◽  
Novel Coronavirus

Background: The outbreak of severe acute respiratory syndrome β-coronavirus 2 (SARS-CoV-2) has the potential to become a long-lasting global health crisis. The number of people infected with the novel coronavirus has surpassed 22 million globally, resulting in over 700,000 deaths with more than 15 million people having recovered (https://covid19.who.int). Enormous efforts are underway for rapid vaccine and treatment developments. Amongst the many ways of tackling the novel coronavirus disease 2019 (COVID-19) pandemic, extracellular vesicles (EVs) are emerging. Summary: EVs are lipid bilayer-enclosed structures secreted from all types of cells, including those lining the respiratory tract. They have established roles in lung immunity and are involved in the pathogenesis of various lung diseases, including viral infection. In this review, we point out the roles and possible contribution of EVs in viral infections, as well as ongoing EV-based approaches for the treatment of COVID-19, including clinical trials. Key Messages: EVs share structural similarities to viruses and recent findings demonstrate that viruses exploit EVs for cellular exit and EVs exploit viral entry mechanisms for cargo delivery. Moreover, EV-virus interplay could be exploited for future antiviral drug and vaccine development. EV-based therapies, especially the mesenchymal stem cell-derived EVs, are being intensively studied for the treatment of COVID-19.

scholarly journals Protective Immunity against SARS Subunit Vaccine Candidates Based on Spike Protein: Lessons for Coronavirus Vaccine Development

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Atin Khalaj-Hedayati
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Subunit Vaccine ◽  
Vaccine Development ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Universal Vaccine ◽  
Health Security ◽  
Vaccine Candidates ◽  
Novel Coronavirus

The recent outbreak of the novel coronavirus disease, COVID-19, has highlighted the threat that highly pathogenic coronaviruses have on global health security and the imminent need to design an effective vaccine for prevention purposes. Although several attempts have been made to develop vaccines against human coronavirus infections since the emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003, there is no available licensed vaccine yet. A better understanding of previous coronavirus vaccine studies may help to design a vaccine for the newly emerged virus, SARS-CoV-2, that may also cover other pathogenic coronaviruses as a potentially universal vaccine. In general, coronavirus spike protein is the major antigen for the vaccine design as it can induce neutralizing antibodies and protective immunity. By considering the high genetic similarity between SARS-CoV and SARS-CoV-2, here, protective immunity against SARS-CoV spike subunit vaccine candidates in animal models has been reviewed to gain advances that can facilitate coronavirus vaccine development in the near future.

scholarly journals Increased susceptibility of human endothelial cells to infections by SARS-CoV-2 variants

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Julian U. G. Wagner ◽  
Denisa Bojkova ◽  
Mariana Shumliakivska ◽  
Guillermo Luxán ◽  
Luka Nicin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
Cell Number ◽  
Spike Protein ◽  
Human Endothelial Cells ◽  
Health Crisis ◽  
Novel Coronavirus ◽  
Umbilical Vein Endothelial Cells

AbstractCoronavirus disease 2019 (COVID-19) spawned a global health crisis in late 2019 and is caused by the novel coronavirus SARS-CoV-2. SARS-CoV-2 infection can lead to elevated markers of endothelial dysfunction associated with higher risk of mortality. It is unclear whether endothelial dysfunction is caused by direct infection of endothelial cells or is mainly secondary to inflammation. Here, we investigate whether different types of endothelial cells are susceptible to SARS-CoV-2. Human endothelial cells from different vascular beds including umbilical vein endothelial cells, coronary artery endothelial cells (HCAEC), cardiac and lung microvascular endothelial cells, or pulmonary arterial cells were inoculated in vitro with SARS-CoV-2. Viral spike protein was only detected in HCAECs after SARS-CoV-2 infection but not in the other endothelial cells tested. Consistently, only HCAEC expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), required for virus infection. Infection with the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.2 resulted in significantly higher levels of viral spike protein. Despite this, no intracellular double-stranded viral RNA was detected and the supernatant did not contain infectious virus. Analysis of the cellular distribution of the spike protein revealed that it co-localized with endosomal calnexin. SARS-CoV-2 infection did induce the ER stress gene EDEM1, which is responsible for clearance of misfolded proteins from the ER. Whereas the wild type of SARS-CoV-2 did not induce cytotoxic or pro-inflammatory effects, the variant B.1.1.7 reduced the HCAEC cell number. Of the different tested endothelial cells, HCAECs showed highest viral uptake but did not promote virus replication. Effects on cell number were only observed after infection with the variant B.1.1.7, suggesting that endothelial protection may be particularly important in patients infected with this variant.

scholarly journals COVID-19: Characteristics and Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 206 ◽  
Author(s):  
Rameswari Chilamakuri ◽  
Saurabh Agarwal
Keyword(s):  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
World Health ◽  
Pharmacological Intervention ◽  
Multiple Treatment ◽  
The Usa ◽  
Novel Coronavirus

Novel coronavirus (COVID-19 or 2019-nCoV or SARS-CoV-2), which suddenly emerged in December 2019 is still haunting the entire human race and has affected not only the healthcare system but also the global socioeconomic balances. COVID-19 was quickly designated as a global pandemic by the World Health Organization as there have been about 98.0 million confirmed cases and about 2.0 million confirmed deaths, as of January 2021. Although, our understanding of COVID-19 has significantly increased since its outbreak, and multiple treatment approaches and pharmacological interventions have been tested or are currently under development to mitigate its risk-factors. Recently, some vaccine candidates showed around 95% clinical efficacy, and now receiving emergency use approvals in different countries. US FDA recently approved BNT162 and mRNA-1273 vaccines developed by Pfizer/BioNTech and Moderna Inc. for emergency use and vaccination in the USA. In this review, we present a succinct overview of the SARS-CoV-2 virus structure, molecular mechanisms of infection, COVID-19 epidemiology, diagnosis, and clinical manifestations. We also systematize different treatment strategies and clinical trials initiated after the pandemic outbreak, based on viral infection and replication mechanisms. Additionally, we reviewed the novel pharmacological intervention approaches and vaccine development strategies against COVID-19. We speculate that the current pandemic emergency will trigger detailed studies of coronaviruses, their mechanism of infection, development of systematic drug repurposing approaches, and novel drug discoveries for current and future pandemic outbreaks.

scholarly journals Structural analysis of COVID-19 spike protein in recognizing the ACE2 receptor of different mammalian species and its susceptibility to viral infection.

2020 ◽  
Author(s):  
Tirthankar Koley ◽  
Shivani Madaan ◽  
Sanghati Roy Chowdhury ◽  
Manoj Kumar ◽  
Punit Kaur ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Interaction Analysis ◽  
Mammalian Species ◽  
Protein Docking ◽  
Glycosylation Site ◽  
Spike Protein ◽  
Amino Acid Residues ◽  
New Public Health ◽  
Potential Mode ◽  
Novel Coronavirus

Abstract The pandemic COVID-19 caused by a novel coronavirus SARS-CoV-2 spread worldwide as a new public health emergency. The SARS-CoV-2 infects humans by binding to glycosylated ACE2 receptor present in the inner lining of the lungs, heart, intestine and kidney. The COVID spike 2 protein recognizes the ACE2 receptor at the N-terminal helices of the metalloprotease domain. The residues Gln24, Thr27, Lys31, His34, Glu37, Asp38, Tyr41, Gln42 from helix α1; Leu79, Met82, Tyr83 from helix α2 and Gln325, Glu329, Asn330, Lys353 from loop connecting β4 and β5 strands form a concave surface surrounded by four glycosylation sites Asn53, Asn90, Asn103 and Asn322 form interactions with the spike protein. However, no significant data on the susceptibility of animals for infection or transmission. Therefore, we performed the comparative protein-protein docking analysis using the crystal structure of spike protein and homology models of the ACE2 receptor from 16 commonly found mammalian species to understand the potential mode of spike binding. Our comprehensive sequence and structure-based interaction analysis revealed the natural substitution of amino acid residues Gln24, His34, Phe40 and Met82 in the N-terminal α1 and α2 helices results in loss of crucial network of hydrogen-bonded and hydrophobic interactions with spike 2 RBD domain. Besides, the absence of N-linked glycosylation site Asn103 in other mammals further reduces the binding affinity between spike and ACE2 receptor. Hence, these changes explain the differences in the susceptibility and host pathogenesis in other mammalian species.

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