scholarly journals A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation

Scientifica ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Jyotirmoy Sarker ◽  
Pritha Das ◽  
Sabarni Sarker ◽  
Apurba Kumar Roy ◽  
A. Z. M. Ruhul Momen
Keyword(s):  
Host Cell ◽  
Serine Protease ◽  
Infection Rate ◽  
Spike Protein ◽  
Host Cell Membrane ◽  
Protein Activation ◽  
Host Membrane ◽  
Expression Rate ◽  
Transmembrane Serine Protease ◽  
Potential Inhibitors

SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, uses the host cell membrane receptor angiotensin-converting enzyme 2 (ACE2) for anchoring its spike protein, and the subsequent membrane fusion process is facilitated by host membrane proteases. Recent studies have shown that transmembrane serine protease 2 (TMPRSS2), a protease known for similar role in previous coronavirus infections, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), is responsible for the proteolytic cleavage of the SARS-CoV-2 spike protein, enabling host cell fusion of the virus. TMPRSS2 is known to be expressed in the epithelial cells of different sites including gastrointestinal, respiratory, and genitourinary system. The infection site of the SARS-CoV-2 correlates with the coexpression sites of ACE2 and TMPRSS2. Besides, age-, sex-, and comorbidity-associated variation in infection rate correlates with the expression rate of TMPRSS2 in those groups. These findings provide valid reasons for the assumption that inhibiting TMPRSS2 can have a beneficial effect in reducing the cellular entry of the virus, ultimately affecting the infection rate and case severity. Several drug development studies are going on to develop potential inhibitors of the protease, using both conventional and computational approaches. Complete understanding of the biological roles of TMPRSS2 is necessary before such therapies are applied.

scholarly journals Exaptation of Retroviral Syncytin for Development of Syncytialized Placenta, Its Limited Homology to the SARS-CoV-2 Spike Protein and Arguments against Disturbing Narrative in the Context of COVID-19 Vaccination

Biology ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 238
Author(s):  
Malgorzata Kloc ◽  
Ahmed Uosef ◽  
Jacek Z. Kubiak ◽  
Rafik M. Ghobrial
Keyword(s):  
Cell Membrane ◽  
Host Cell ◽  
Envelope Glycoprotein ◽  
Mammalian Species ◽  
Viral Envelope ◽  
Spike Protein ◽  
Mammalian Evolution ◽  
Trophoblast Cells ◽  
Host Cell Membrane ◽  
Uterine Endometrium

Human placenta formation relies on the interaction between fused trophoblast cells of the embryo with uterine endometrium. The fusion between trophoblast cells, first into cytotrophoblast and then into syncytiotrophoblast, is facilitated by the fusogenic protein syncytin. Syncytin derives from an envelope glycoprotein (ENV) of retroviral origin. In exogenous retroviruses, the envelope glycoproteins coded by env genes allow fusion of the viral envelope with the host cell membrane and entry of the virus into a host cell. During mammalian evolution, the env genes have been repeatedly, and independently, captured by various mammalian species to facilitate the formation of the placenta. Such a shift in the function of a gene, or a trait, for a different purpose during evolution is called an exaptation (co-option). We discuss the structure and origin of the placenta, the fusogenic and non-fusogenic functions of syncytin, and the mechanism of cell fusion. We also comment on an alleged danger of the COVID-19 vaccine based on the presupposed similarity between syncytin and the SARS-CoV-2 spike protein.

scholarly journals Interactions of Peptide Coated Gold Nanoparticles with Spike Protein of the SARS-CoV-2: A Basis for Design of a Simple and Rapid Detection Tool

2020 ◽  
Author(s):  
Nitu Verma ◽  
Yogesh Badhe ◽  
Rakesh Gupta ◽  
Auhin Maparu ◽  
Beena Rai
Keyword(s):  
Gold Nanoparticles ◽  
Host Cell ◽  
Potential Of Mean Force ◽  
Spike Protein ◽  
Coarse Grained ◽  
Dynamic Simulations ◽  
Host Cell Membrane ◽  
Preferential Binding ◽  
Set Up ◽  
Force Calculation

<p>The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic which not only created a situation of dealing with public health emergency but also triggered the financial crisis of international concern. The current situation demands rapid, convenient and reliable diagnosis of the disease to downregulate its spread. Primary method of diagnosis presently being used, such as nucleic acid testing (RT-PCR), CT scans etc. involve time-consuming advanced machinery for imaging/ RNA replication and highly skilled technicians which could be only done in a laboratory set-up. A rapid, simple yet selective naked eye detection methodology that does not require any advanced instrumental techniques is highly desirable. </p> <p>In this study, we report computational results which could form the basis of a simple and rapid strategy for the detection of SARS-Cov-2 using peptide (screened from angiotensin-converting enzyme 2 (ACE2) receptor of host cell) functionalized gold nanoparticles (GNPs). This is based on the preferential binding of viral spike (S) protein to ACE2 receptor situated on the surface of the host cell membrane by which the virus gains access to the host cell. The interaction of peptide coated GNPs with spike protein has been investigated using coarse grained molecular dynamic simulations. The potential of mean force calculation of spike protein confirmed strong binding between peptide and receptor binding domain (RBD) of spike protein. The results presented here demonstrate the potential of this peptide coated GNPs-based system in the development of convenient sensors for the clinical diagnosis. </p>

scholarly journals Phytoconstituents of Zingiber officinale Targeting Host viral Protein Interaction at Entry Point of SARS CoV 2 A Molecular Docking Study

2020 ◽  
Vol 5 (4) ◽  
pp. 268-277
Author(s):  
Rakesh Kumar Sharma ◽  
Ankita Singh Chakotiya
Keyword(s):  
Host Cell ◽  
Serine Protease ◽  
Zingiber Officinale ◽  
Docking Study ◽  
Critical Issue ◽  
Evidence Base ◽  
Entry Point ◽  
Spike Protein ◽  
Molecular Docking Study ◽  
Microbial Infections

Current COVID 19 outbreak is a critical issue in safeguarding public health worldwide. The lack of prophylactic drugs, vaccine and effective antiviral and other supporting therapies has prompted researchers to look for promising leads against the virus. Metabolic pathways and biochemicals involved in pathophysiology of SARS-CoV-2 can be targeted to find out effective inhibitor molecules acting at the entry point of infection. SARS-CoV-2 uses their Spike protein to dock at ACE2 and the serine protease, TMPRSS2 of host cell for Spike protein priming to get entry into the host cell. In the present study phytochemicals from Zingiber officinale were evaluated to find their binding with these proteins by conducting ligand-receptor binding docking study with AutoDockVina. The structures were observed by visualizing softwares Pymol to determine unique amino acids of receptor proteins. Physicochemical properties of phytochemicals and chemotherapeutic markers were assessed with Molinspiration tool. Docking study revealed that Gingerenone (-5.87 kcal/mol) and Zingiberene (-5.77 kcal/mol) have shown effective binding affinity towards ACE2. Shoagol (-5.72 kcal/mol), Zingerone (-5.79 kcal/mol) and Zingiberene (-5.52 kcal/mol) have shown higher binding with extracellular domain of serine protease TMPRSS2. Zingiberene scored significant binding energy of -6.23 kcal/mol with Spike protein of SARS-CoV-2. This study provides an evidence base to the experiential learning about use of Zingiber officinale in microbial infections. Once further validated, it may lead to development of herbal based anti-viral adjuvants.

COVID 19: Camostat and The Role of Serine Protease Entry Inhibitor TMPRSS2

2020 ◽  
Author(s):  
Stefan Bittmann
Keyword(s):  
Host Cell ◽  
Serine Protease ◽  
Cellular Protein ◽  
Host Cells ◽  
The Novel ◽  
Robert Koch Institute ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

According to the latest research, the novel coronavirus uses the protein angiotensin-converting enzyme 2 (ACE-2) as a receptor for docking to the host cell. Essential for entry is the priming of the spike (S) protein of the virus by host cell proteases. A broadly based team led by infection biologists from the German Primate Centre and with the participation of the Charité Hospital in Berlin, the Hanover Veterinary University Foundation, the BG-UnfallklinikMurnau, the LMU Munich, the Robert Koch Institute and the German Centre for Infection Research wanted to find out how SARS-CoV-2 enters host cells and how this process can be blocked [1]. They have published their findings in the journal "Cell" [1]. The team of scientists was initially able to confirm that SARS-CoV-2 docks to the host cell via the ACE-2 receptor. They also identified Transmembrane serine protease 2 (TMPRSS2) as the cellular protein responsible for entry into the cell [1-3].

scholarly journals Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Esteban Dodero-Rojas ◽  
Jose N Onuchic ◽  
Paul Charles Whitford
Keyword(s):  
Host Cell ◽  
Conformational Change ◽  
Cell Invasion ◽  
Large Scale ◽  
Control Cell ◽  
Spike Protein ◽  
Fusion Peptides ◽  
Structural Framework ◽  
Host Membrane ◽  
Transmembrane Pores

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. While infection relies on this transition between the prefusion and postfusion conformations, there has yet to be a biophysical characterization reported for this rearrangement. That is, structures are available for the endpoints, though the intermediate conformational processes have not been described. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. With the current lack of data on the pre-to-post transition, the precise role of glycans during cell invasion has also remained unclear. To provide an initial mechanistic description of the pre-to-post rearrangement, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans can induce a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. In contrast, in the absence of glycans, the viral particle would likely fail to enter the host. This analysis reveals how the glycosylation state can regulate infectivity, while providing a much-needed structural framework for studying the dynamics of this pervasive pathogen.

scholarly journals Sterically-Confined Rearrangements of SARS-CoV-2 Spike Protein Control Cell Invasion

2021 ◽  
Author(s):  
Esteban Dodero-Rojas ◽  
José N. Onuchic ◽  
Paul C. Whitford
Keyword(s):  
Host Cell ◽  
Conformational Change ◽  
Cell Invasion ◽  
Large Scale ◽  
Control Cell ◽  
Spike Protein ◽  
Fusion Peptides ◽  
Host Membrane ◽  
Transmembrane Pores

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. Despite the large number of glycosylation sites, until now, the specific role of glycans during cell invasion has been unclear. Here, we propose that glycosylation is needed to provide sufficient time for the fusion peptides to reach the host membrane, otherwise the viral particle would fail to enter the host. To understand this process, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans induces a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. This previously-unrecognized role of glycans reveals how the glycosylation state can regulate infectivity of this pervasive pathogen.

scholarly journals TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Naoko Iwata-Yoshikawa ◽  
Tadashi Okamura ◽  
Yukiko Shimizu ◽  
Hideki Hasegawa ◽  
Makoto Takeda ◽  
...  
Keyword(s):  
Animal Models ◽  
Serine Protease ◽  
Spike Protein ◽  
Lung Pathology ◽  
Murine Models ◽  
Virus Spread ◽  
Highly Pathogenic ◽  
Coronavirus Infection ◽  
Transmembrane Serine Protease

ABSTRACT Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology. IMPORTANCE Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.

Genomics-guided identification of potential modulators of SARS-CoV-2 entry proteases, TMPRSS2 and Cathepsins B/L

2021 ◽  
Author(s):  
Kartikay Prasad ◽  
Vijay Kumar
Keyword(s):  
Retinoic Acid ◽  
Host Cell ◽  
Serine Protease ◽  
Deep Understanding ◽  
Cysteine Proteases ◽  
Regulatory Elements ◽  
Host Cells ◽  
Spike Protein ◽  
Therapeutic Benefits ◽  
Human Proteins

Abstract The entry of SARS-CoV-2 into host cells requires the activation of its spike protein by host cell proteases. The serine protease, transmembrane serine protease 2 (TMPRSS2) and cysteine proteases, cathepsins B, L (CTSB/L) activate spike protein and enabling SARS-CoV-2 entry to the host cell through two completely different and independent pathways. Given that the uncertainty of how SARS-CoV-2 infects and kills, the need for a deep understanding of SARS-CoV-2 biology is imperative. Herein, we performed genomic-guided meta-analysis to identify upstream regulatory elements altering the expression of TMPRSS2 and CTSB/L genes. Further, drugs and medicinal compounds were identified based on their effects on gene expression signatures of the modulators of TMPRSS2 and CTSB/L genes. Using this strategy, estradiol and retinoic acid have been identified as putative SARS-CoV-2 alleviation agents. Further, we analysed drug-gene and gene-gene interaction network using 332 human targets of SARS-CoV-2 proteins. The network results indicate that out of 332 human proteins, estradiol interacts with 135 (41%) and retinoic acid interacts with 40 (12%) proteins. Interestingly, a combination of both estradiol and retinoic acid interacts with 153 (46%) of human proteins acting as SARS-CoV-2 targets and affect the functions of nearly all of the SARS-CoV-2 viral proteins, indicating the therapeutic benefits of drug combination therapy. Finally, molecular docking analysis suggest that both the drugs binds to TMPRSS2 and CTSL with the nanomolar to low micromolar affinity. This study, for the first time, reports the molecules like estradiol and retinoic acid as candidate drugs against both the host proteases, TMPRSS2 and CTSB/L. We here thus suggest that these antiviral drugs alone or in combination can simultaneously target both the entry pathways and thus can be considered as a potential treatment option for COVID-19.

scholarly journals Interactions of Peptide Coated Gold Nanoparticles with Spike Protein of the SARS-CoV-2: A Basis for Design of a Simple and Rapid Detection Tool

2020 ◽  
Author(s):  
Nitu Verma ◽  
Yogesh Badhe ◽  
Rakesh Gupta ◽  
Auhin Maparu ◽  
Beena Rai
Keyword(s):  
Gold Nanoparticles ◽  
Host Cell ◽  
Potential Of Mean Force ◽  
Spike Protein ◽  
Coarse Grained ◽  
Dynamic Simulations ◽  
Host Cell Membrane ◽  
Preferential Binding ◽  
Set Up ◽  
Force Calculation

<p>The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic which not only created a situation of dealing with public health emergency but also triggered the financial crisis of international concern. The current situation demands rapid, convenient and reliable diagnosis of the disease to downregulate its spread. Primary method of diagnosis presently being used, such as nucleic acid testing (RT-PCR), CT scans etc. involve time-consuming advanced machinery for imaging/ RNA replication and highly skilled technicians which could be only done in a laboratory set-up. A rapid, simple yet selective naked eye detection methodology that does not require any advanced instrumental techniques is highly desirable. </p> <p>In this study, we report computational results which could form the basis of a simple and rapid strategy for the detection of SARS-Cov-2 using peptide (screened from angiotensin-converting enzyme 2 (ACE2) receptor of host cell) functionalized gold nanoparticles (GNPs). This is based on the preferential binding of viral spike (S) protein to ACE2 receptor situated on the surface of the host cell membrane by which the virus gains access to the host cell. The interaction of peptide coated GNPs with spike protein has been investigated using coarse grained molecular dynamic simulations. The potential of mean force calculation of spike protein confirmed strong binding between peptide and receptor binding domain (RBD) of spike protein. The results presented here demonstrate the potential of this peptide coated GNPs-based system in the development of convenient sensors for the clinical diagnosis. </p>

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