scholarly journals Targeting host cell proteases to prevent SARS-CoV-2 invasion

2020 ◽  
Vol 21 ◽  
Author(s):  
Upinder Kaur ◽  
Sankha Shubhra Chakrabarti ◽  
Bisweswar Ojha ◽  
Bhairav Kumar Pathak ◽  
Amit Singh ◽  
...  
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Standard Of Care ◽  
Caproic Acid ◽  
Factor X ◽  
Angiotensin Converting Enzyme 2 ◽  
Symptomatic Management ◽  
Anticoagulant Drugs ◽  
Definitive Therapy

: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs including several anti-viral drugs is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the trans-membrane serine protease-2 (TMPRSS2) is necessary for fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we discuss the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence as well as hypotheses are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.

Genomic Variations in ORF3a and ORF1ab Genes of SARS-nCoV2 Strain from Southern Pakistan

2020 ◽  
Author(s):  
Rashid Saif ◽  
Aniqa Ejaz ◽  
Tania Mahmood ◽  
Saeeda Zia ◽  
Abdul Rasheed Qureshi
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Binding Capacity ◽  
Its Sequence ◽  
Genomic Variations ◽  
S Gene ◽  
Variation Rate ◽  
Codon Change ◽  
Different Strains

Emergence of COVID-19 pandemic has resulted in 8,578,283 total cases and 456,286 deaths worldwide as of June 19, 2020. We previously analysed genomic variants in two Northern Pakistani SARS-nCoV2 strains against USA and Chinese strains as reference, and hypothesized the putative role of observed variants in low severity of COVID-19 in Pakistan. Due to high variation rate in this virus, we further analysed the whole genome of Southern Pakistani SARS-nCoV2 MT500122 strain (Karachi-Pak) vs NC_045512 (Wuhan1-China) and observed 4 variants (3=SNPs,1=del). Three of variants at g.1604 (del ND447N), SNPs at g.1912 (p.=), g.10582 (p.=) and g.26022 (p.=) in ORF1ab and ORF3a genes respectively. ORF1ab encodes 16 non-structural polyproteins (nsps1-16) and plays role in viral replication. The codon change deletion in its sequence (as observed in MT500122) might have caused conformational alterations particularly in nsp2&5 structures which may obstruct its effectiveness. ORF3a is unique to SARS-nCoV2 and located in-between envelope and spike genes, which assist viral entry into the host cell by interacting with S gene. Alteration in its sequence might have hampered the activation of S gene and affect its binding capacity to host cell ACE2 and NRP1 receptors, which may greatly weaken its pathogenicity in its different strains and hence may vary severity of COVID-19. Nevertheless, intensive data and conclusive wet lab experiments are needed for validating this postulated hypothesis. Moreover, these variants have modifier to silent impact on further 9 genes e.g. M, N, S, E, ORFs 6, 7a, 7b, 8 and 10 as well. Advancements in understanding the role of these Pakistani SARS-nCoV2 genomic variations will be helpful in developing indigenous vaccines, diagnostic kits and drug development.

scholarly journals Genetic variability in the expression of the SARS-CoV-2 host cell entry factors across populations

2020 ◽  
Author(s):  
Lourdes Ortiz-Fernández ◽  
Amr H Sawalha
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Quantitative Measure ◽  
Individual Variability ◽  
Host Cells ◽  
Genetic Determinants ◽  
Angiotensin Converting Enzyme 2 ◽  
African Populations ◽  
Host Cell Entry ◽  
Host Cell Membranes

AbstractThe entry of SARS-CoV-2 into host cells is dependent upon angiotensin-converting enzyme 2 (ACE2), which serves as a functional attachment receptor for the viral spike glycoprotein, and the serine protease TMPRSS2 which allows fusion of the viral and host cell membranes. We devised a quantitative measure to estimate genetic determinants of ACE2 and TMPRSS2 expression and applied this measure to >2,500 individuals. Our data show significant variability in genetic determinants of ACE2 and TMPRSS2 expression among individuals and between populations, and demonstrate a genetic predisposition for lower expression levels of both key viral entry genes in African populations. These data suggest that genetic factors might lead to lower susceptibility for SARS-CoV-2 infection in African populations and that host genetics might help explain inter-individual variability in disease susceptibility and severity of COVID-19.

scholarly journals Gene of the month: TMPRSS2 (transmembrane serine protease 2)

2020 ◽  
Vol 73 (12) ◽  
pp. 773-776 ◽  
Author(s):  
Michelle Thunders ◽  
Brett Delahunt
Keyword(s):  
Serine Protease ◽  
Viral Entry ◽  
Fusion Gene ◽  
Related Gene ◽  
Diverse Range ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Spread ◽  
Transmembrane Serine Protease ◽  
Oncogenic Transcription Factor

Transmembrane serine protease 2 is encoded by the TMPRSS2 gene. The gene is widely conserved and has two isoforms, both being autocatalytically activated from the inactive zymogen form. A fusion gene between the TMPRSS2 gene and ERG (erythroblast-specific-related gene), an oncogenic transcription factor, is the most common chromosomal aberration detected in prostate cancer, responsible for driving carcinogenesis. The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a diverse range of viruses. Both SARS-CoV and SARS-CoV-2 (COVID-19) use angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 to facilitate entry to cells, but with SARS-CoV-2 human-to-human transmission is much higher than SARS-CoV. As TMPRSS2 is expressed outside of the lung, and can therefore contribute to extrapulmonary spread of viruses, it warrants further exploration as a potential target for limiting viral spread and infectivity.

scholarly journals Diabetic Nephropathy and COVID-19: The Potential Role of Immune Actors

2021 ◽  
Vol 22 (15) ◽  
pp. 7762
Author(s):  
Diane Mourad ◽  
Nadim S. Azar ◽  
Sami T. Azar
Keyword(s):  
Diabetic Nephropathy ◽  
Viral Entry ◽  
Type Ii Diabetes ◽  
Potential Role ◽  
Underlying Mechanism ◽  
Type Ii Diabetes Mellitus ◽  
Angiotensin Converting Enzyme 2 ◽  
Neuropilin 1 ◽  
Mitochondrial Glutathione

Nowadays, type II diabetes mellitus, more specifically ensuing diabetic nephropathy, and severe COVID-19 disease are known to be closely associated. The exact mechanisms behind this association are less known. An implication for the angiotensin-converting enzyme 2 remains controversial. Some researchers have started looking into other potential actors, such as neuropilin-1, mitochondrial glutathione, vitamin D, and DPP4. In particular, neuropilin-1 seems to play an important role in the underlying mechanism linking COVID-19 and diabetic nephropathy. We suggest, based on the findings in this review, that its up-regulation in the diabetic kidney facilitates viral entry in this tissue, and that the engagement of both processes leads to a depletion of neuropilin-1, which was demonstrated to be strongly associated with the pathogenesis of DN. More studies are needed to confirm this hypothesis, and research should be directed towards elucidating the potential roles of all these suggested actors and eventually discovering new therapeutic strategies that could reduce the burden of COVID-19 in patients with diabetic nephropathy.

scholarly journals TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 384
Author(s):  
Mai Kishimoto ◽  
Kentaro Uemura ◽  
Takao Sanaki ◽  
Akihiko Sato ◽  
William W. Hall ◽  
...  
Keyword(s):  
Viral Entry ◽  
Vaccine Development ◽  
Spike Protein ◽  
Tissue Tropism ◽  
Type Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Exogenous Expression ◽  
Transmembrane Serine Protease ◽  
The Impact

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.

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 Renin-Angiotensin System Blockade In The Coronavirus Disease 2019 Pandemic

2021 ◽  
Author(s):  
Jordana B Cohen ◽  
Andrew M South ◽  
Hossam A Shaltout ◽  
Matthew R Sinclair ◽  
Matthew A Sparks
Keyword(s):  
Viral Entry ◽  
Renin Angiotensin System ◽  
Adverse Outcomes ◽  
Host Cells ◽  
Protective Effects ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Epidemiologic Evidence

ABSTRACT In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counter-regulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.

scholarly journals ACE2 enzymatic role in the SARS-CoV-2 activation: a perspective through the evolutionary promiscuity and substrate diversity of enzymes

2021 ◽  
Vol 4 (4) ◽  
pp. 581-587
Author(s):  
Angela Madalina Lazar
Keyword(s):  
Host Cell ◽  
Recent Work ◽  
Viral Entry ◽  
Mortality Rates ◽  
Future Design ◽  
The Future ◽  
Key Enzyme ◽  
High Infectivity

The SARS-CoV-2 is an RNA B type β-coronavirus that distinguishes itself from previous coronaviruses by its high infectivity and mortality rates. The mechanism of viral entry into the host cell via ACE2 is currently under research. Several proteases have been nominated to activate the virus but identifying the exact enzyme/enzymes is missing.   Moreover, recent work suggests that TMPRSS2 cannot be the enzyme to cleave the SARS-CoV-2 spike or that multiple proteases contribute to SARS-CoV-2 activation. The multitude of proteases that have been nominated to activate the virus suggests that the consensual identification of the precise, key enzyme is still missing. In this context, we synthesize the current controversies regarding the putative enzymes involved in SARS-CoV-2 infectivity and analyze whether ACE2 could have unexpected enzymatic roles in this process, besides its acknowledged receptor role. We hypothesize that ACE2 plays an enzymatic role as well in SARS-CoV-2 activation. Understanding the exact roles of ACE2 in COVID-19 is capital for the future design of specific, efficient therapies and deserves dedicated research. Our conviction is therefore not "if", “but” "when" will the researchers start to wonder about what is hidden behind the apparent only role of ACE2 as a receptor for SARS-CoV-2.

Understanding the Role of Corona Virus based on Current Scientific Evidence - A Review with Emerging Importance in Pandemic

2020 ◽  
Vol 15 (2) ◽  
pp. 89-103
Author(s):  
Suman K. Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Host Cell ◽  
Scientific Evidence ◽  
Antibody Therapy ◽  
Cell Receptor ◽  
Spike Protein ◽  
Virus Infectivity ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Cell Receptor ◽  
Antiviral Medications

: Coronavirus disease is a potentially deadly disease and of significant apprehension for global communal health because of its lethality. Vaccines and antiviral medications are still under trial to prevent or treat human coronavirus (HCoV) till date. The virus HCoV originated in 2003, SARS-CoV, which causes respiratory syndrome having distinctive pathogenesis and infections of the respiratory tract. A mechanism was projected for the evolution of SARS virus, and a handy association with bats was found. When this virus reaches the respective host system, the infection starts with spike protein binding to its complementary receptor of the host cell. The coronavirus spike protein’s association with its host cell receptor complement is crucial in deciding the virus infectivity, tissue tropism and species variety. Recent studies show that SARS Coronavirus 2 or COVID-19 requires protease to get into cells, offering a new therapeutic target. Distinctive attention and exertions should be given to defending or reducing transmission in vulnerable populaces, including those directly associated with caregiving and treatment and also aged one. Researchers are planning to develop a vaccine for COVID-19, and in this approach are also considered developing a vaccine that sensitizes our immune system preventing from this pandemic. The present review focuses on the role of S-spike protein in COVID-19, which helps the virus intruding the enzyme ACE2 (Angiotensin-Converting Enzyme 2). Passive antibody therapy is an additional alternative to use blood donors from hale and hearty people who have already recovered from COVID-19 and therapeutic advancement in handling the COVID-19 pandemic.

scholarly journals Cardiac Involvement in COVID-19

Kardiologiia ◽  
2021 ◽  
Vol 61 (4) ◽  
pp. 15-23
Author(s):  
A. B. Sugraliyev
Keyword(s):  
Viral Entry ◽  
Cardiac Involvement ◽  
Viral Disease ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Number Of Patients ◽  
Coronavirus Infection ◽  
Novel Coronavirus ◽  
Inflammatory Syndrome

The novel coronavirus infection, COVID-19, is a highly contagious viral disease associated with acute, severe respiratory syndrome, which is based on the development of pronounced thrombo-inflammatory syndrome. As the number of patients with COVID-19 increased, heart damage has been reported, especially in patients with severe and critical COVID-19. This review describes the role of angiotensin-converting enzyme 2 receptor in the regulation of viral entry, the variety of damages to the heart and coronary arteries, and the importance of arterial hypertension and of the use of renin-angiotensin-aldosterone system inhibitors in the prognosis of patients with COVID-19.

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