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.

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 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.

MANUSCRIPT EVIDENCE FOR ALPHABET-SWITCHING IN THE WORKS OF CICERO: COMMON NOUNS AND ADJECTIVES

2018 ◽  
Vol 68 (2) ◽  
pp. 498-516
Author(s):  
Neil O'Sullivan
Keyword(s):  
Recent Work ◽  
Code Switching ◽  
Consistent Pattern ◽  
Current Interest ◽  
Reliable Transmission ◽  
Accurate Record ◽  
The Way

Of the hundreds of Greek common nouns and adjectives preserved in our MSS of Cicero, about three dozen are found written in the Latin alphabet as well as in the Greek. So we find, alongside συμπάθεια, also sympathia, and ἱστορικός as well as historicus. This sort of variation has been termed alphabet-switching; it has received little attention in connection with Cicero, even though it is relevant to subjects of current interest such as his bilingualism and the role of code-switching and loanwords in his works. Rather than addressing these issues directly, this discussion sets out information about the way in which the words are written in our surviving MSS of Cicero and takes further some recent work on the presentation of Greek words in Latin texts. It argues that, for the most part, coherent patterns and explanations can be found in the alphabetic choices exhibited by them, or at least by the earliest of them when there is conflict in the paradosis, and that this coherence is evidence for a generally reliable transmission of Cicero's original choices. While a lack of coherence might indicate unreliable transmission, or even an indifference on Cicero's part, a consistent pattern can only really be explained as an accurate record of coherent alphabet choice made by Cicero when writing Greek words.

Tryptophan-Niacin Metabolism in Rat with Puromycin Aminonucleoside-Induced Nephrosis

2006 ◽  
Vol 76 (1) ◽  
pp. 28-33 ◽  
Author(s):  
Yukari Egashira ◽  
Shin Nagaki ◽  
Hiroo Sanada
Keyword(s):  
Body Weight ◽  
Urinary Excretion ◽  
Enzyme Activities ◽  
Treated Group ◽  
Control Group ◽  
Puromycin Aminonucleoside ◽  
Low Level ◽  
Key Enzyme

We investigated the change of tryptophan-niacin metabolism in rats with puromycin aminonucleoside PAN-induced nephrosis, the mechanisms responsible for their change of urinary excretion of nicotinamide and its metabolites, and the role of the kidney in tryptophan-niacin conversion. PAN-treated rats were intraperitoneally injected once with a 1.0% (w/v) solution of PAN at a dose of 100 mg/kg body weight. The collection of 24-hour urine was conducted 8 days after PAN injection. Daily urinary excretion of nicotinamide and its metabolites, liver and blood NAD, and key enzyme activities of tryptophan-niacin metabolism were determined. In PAN-treated rats, the sum of urinary excretion of nicotinamide and its metabolites was significantly lower compared with controls. The kidneyα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) activity in the PAN-treated group was significantly decreased by 50%, compared with the control group. Although kidney ACMSD activity was reduced, the conversion of tryptophan to niacin tended to be lower in the PAN-treated rats. A decrease in urinary excretion of niacin and the conversion of tryptophan to niacin in nephrotic rats may contribute to a low level of blood tryptophan. The role of kidney ACMSD activity may be minimal concerning tryptophan-niacin conversion under this experimental condition.

Challenges of Fear Conditioning Research in the Age of RDoC

2017 ◽  
Vol 225 (3) ◽  
pp. 189-199 ◽  
Author(s):  
Tina B. Lonsdorf ◽  
Jan Richter
Keyword(s):  
Fear Conditioning ◽  
Clinical Diagnosis ◽  
Research Domain Criteria ◽  
Major Focus ◽  
The Future ◽  
Definition Of ◽  
Methodological Considerations ◽  
Research Domain

Abstract. As the criticism of the definition of the phenotype (i.e., clinical diagnosis) represents the major focus of the Research Domain Criteria (RDoC) initiative, it is somewhat surprising that discussions have not yet focused more on specific conceptual and procedural considerations of the suggested RDoC constructs, sub-constructs, and associated paradigms. We argue that we need more precise thinking as well as a conceptual and methodological discussion of RDoC domains and constructs, their interrelationships as well as their experimental operationalization and nomenclature. The present work is intended to start such a debate using fear conditioning as an example. Thereby, we aim to provide thought-provoking impulses on the role of fear conditioning in the age of RDoC as well as conceptual and methodological considerations and suggestions to guide RDoC-based fear conditioning research in the future.

The Role of Tradeoff Salience and Connectedness to the Future Self

2011 ◽  
Author(s):  
Daniel Bartels ◽  
Oleg Urminsky ◽  
Shane Frederick
Keyword(s):  
The Future ◽  
Future Self
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