scholarly journals ACE2 receptor, TRL-4 and SARS CoV-2: Do long acting opioids and opioid antagonists have potential for therapy?

2020 ◽  
Author(s):  
Marie Eagleton ◽  
Siobhan Stokes ◽  
Fiona Fenton ◽  
Eamon Keenan
Keyword(s):  
Therapeutic Potential ◽  
Transmembrane Protein ◽  
Protein A ◽  
Cell Receptor ◽  
Opioid Antagonists ◽  
Treatment And Prevention ◽  
Host Cell Receptor ◽  
Main Host ◽  
Low Incidence ◽  
Long Acting

Despite the advent of a vaccine, broadening the arsenal of drugs effective in the treatment and prevention of COVID-19 disease remains critical in the global effort to control the SARSCoV2 pandemic. Opioids and opioid antagonists may have a role in treating and in the prevention of this disease based on a number of observations: an unexpectedly low incidence of COVID-19 has been observed in patients treated for opioid dependency with long acting opioid drugs such as methadone; opioids bind to the ACE2 transmembrane protein, a molecule that is widely considered to be main host cell receptor for SARS CoV2 cell entry; opioids have systemic immunomodulatory effects which may influence the response to the virus; studies aimed at repurposing drugs for treatment of COVID-19 have identified that opioids have therapeutic potential and finally there are ongoing trials of some of these drugs. The interaction of long acting opioids or opioid antagonists with the ACE2 receptor and the possible effects on TLR4 function in SARS CoV2 infection should be given serious consideration when developing effective therapies.

scholarly journals ACE2 receptor, TRL-4 and SARS CoV-2: Do long acting opioids and opioid antagonists have potential for therapy?

2021 ◽  
Author(s):  
Marie Eagleton ◽  
Siobhan Stokes ◽  
Fiona Fenton ◽  
Eamon Keenan
Keyword(s):  
Therapeutic Potential ◽  
Transmembrane Protein ◽  
Protein A ◽  
Cell Receptor ◽  
Opioid Antagonists ◽  
Treatment And Prevention ◽  
Host Cell Receptor ◽  
Main Host ◽  
Low Incidence ◽  
Long Acting

Despite the advent of a vaccine, broadening the arsenal of drugs effective in the treatment and prevention of COVID-19 disease remains critical in the global effort to control the SARSCoV2 pandemic. Opioids and opioid antagonists may have a role in treating and in the prevention of this disease based on a number of observations: an unexpectedly low incidence of COVID-19 has been observed in patients treated for opioid dependency with long acting opioid drugs such as methadone; opioids bind to the ACE2 transmembrane protein, a molecule that is widely considered to be main host cell receptor for SARS CoV2 cell entry; opioids have systemic immunomodulatory effects which may influence the response to the virus; studies aimed at repurposing drugs for treatment of COVID-19 have identified that opioids have therapeutic potential and finally there are ongoing trials of some of these drugs. The interaction of long acting opioids or opioid antagonists with the ACE2 receptor and the possible effects on TLR4 function in SARS CoV2 infection should be given serious consideration when developing effective therapies. Note an updated version of this preprint is under review with the British Journal of Anaesthesia

scholarly journals A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Leo Hanke ◽  
Hrishikesh Das ◽  
Daniel J. Sheward ◽  
Laura Perez Vidakovics ◽  
Egon Urgard ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transgenic Mouse Model ◽  
Viral Antigens ◽  
Host Cell Receptor ◽  
Virus Escape ◽  
Therapeutic Molecules

AbstractAntibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer–dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.

scholarly journals The utility of native MS for understanding the mechanism of action of repurposed therapeutics in COVID-19: heparin as a disruptor of the SARS-CoV-2 interaction with its host cell receptor

2020 ◽  
Author(s):  
Yang Yang ◽  
Yi Du ◽  
Igor A. Kaltashov
Keyword(s):  
Host Cell ◽  
Gas Phase ◽  
Viral Entry ◽  
Protein A ◽  
Cell Receptor ◽  
Critical Element ◽  
S Protein ◽  
Host Cell Receptor ◽  
Native Ms ◽  
Gas Phase Ion

ABSTRACTThe emergence and rapid proliferation of the novel coronavirus (SARS-CoV-2) resulted in a global pandemic, with over six million cases and nearly four hundred thousand deaths reported world-wide by the end of May 2020. A rush to find the cures prompted re-evaluation of a range of existing therapeutics vis-à-vis their potential role in treating COVID-19, placing a premium on analytical tools capable of supporting such efforts. Native mass spectrometry (MS) has long been a tool of choice in supporting the mechanistic studies of drug/therapeutic target interactions, but its applications remain limited in the cases that involve systems with a high level of structural heterogeneity. Both SARS-CoV-2 spike protein (S-protein), a critical element of the viral entry to the host cell, and ACE2, its docking site on the host cell surface, are extensively glycosylated, making them challenging targets for native MS. However, supplementing native MS with a gas-phase ion manipulation technique (limited charge reduction) allows meaningful information to be obtained on the non-covalent complexes formed by ACE2 and the receptor-binding domain (RBD) of the S-protein. Using this technique in combination with molecular modeling also allows the role of heparin in destabilizing the ACE2/RBD association to be studied, providing critical information for understanding the molecular mechanism of its interference with the virus docking to the host cell receptor. Both short (pentasaccharide) and relatively long (eicosasaccharide) heparin oligomers form 1:1 complexes with RBD, indicating the presence of a single binding site. This association alters the protein conformation (to maximize the contiguous patch of the positive charge on the RBD surface), resulting in a notable decrease of its ability to associate with ACE2. The destabilizing effect of heparin is more pronounced in the case of the longer chains due to the electrostatic repulsion between the low-pI ACE2 and the heparin segments not accommodated on the RBD surface. In addition to providing important mechanistic information on attenuation of the ACE2/RBD association by heparin, the study demonstrates the yet untapped potential of native MS coupled to gas-phase ion chemistry as a means of facilitating rational repurposing of the existing medicines for treating COVID-19.Abstract Figure

scholarly journals Protocols for dentists during Covid-19 pandemic

2020 ◽  
Vol 6 (2) ◽  
pp. 101-108
Author(s):  
Pratima Srivastava ◽  
Abhinav Kumar ◽  
Abhineet Kumar
Keyword(s):  
Diagnostic Marker ◽  
Cell Receptor ◽  
Converting Enzyme ◽  
Wuhan City ◽  
Angiotensin Converting Enzyme 2 ◽  
Face To Face ◽  
Host Cell Receptor ◽  
Main Host ◽  
The Face ◽  
Dental Professionals

A novel β-coronavirus (COVID-19) caused severe and even fetal pneumonia explored in a seafood market of Wuhan city, Hubei province, China, and rapidly spread to other provinces of China and other countries across the globe. COVID-19 declared as pandemic in Feb 2020’. COVID-19 was different from SARS-CoV, but shared the same host receptor the human angiotensin-converting enzyme 2 (ACE2). It has been documented that ACE2 is the main host cell receptor of COVID-19 virus and plays a crucial role in the entry of virus into the cell to cause the fatal infection. Interestingly, it has been found that ACE2 receptor are highly enriched in epithelial cells of tongue and saliva can act as a diagnostic marker for detecting virus. Dental personnel are expose to tremendous risk of COVID-19 infection due to the face-to-face communication and the exposure to saliva, blood, and other body fluids etc. Dental professionals plays great roles in preventing the transmission of COVID-19.

scholarly journals Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential

2021 ◽  
Vol 22 (13) ◽  
pp. 6707
Author(s):  
Neale Harrison ◽  
Chek Ziu Koo ◽  
Michael G. Tomlinson
Keyword(s):  
Protein Sequence ◽  
Intracellular Trafficking ◽  
Therapeutic Potential ◽  
Transmembrane Protein ◽  
Protein A ◽  
Ectodomain Shedding ◽  
Protein Substrates ◽  
Published Evidence ◽  
A Disintegrin And Metalloproteinase ◽  
Partner Proteins

The ubiquitously expressed transmembrane protein a disintegrin and metalloproteinase 10 (ADAM10) functions as a “molecular scissor”, by cleaving the extracellular regions from its membrane protein substrates in a process termed ectodomain shedding. ADAM10 is known to have over 100 substrates including Notch, amyloid precursor protein, cadherins, and growth factors, and is important in health and implicated in diseases such as cancer and Alzheimer’s. The tetraspanins are a superfamily of membrane proteins that interact with specific partner proteins to regulate their intracellular trafficking, lateral mobility, and clustering at the cell surface. We and others have shown that ADAM10 interacts with a subgroup of six tetraspanins, termed the TspanC8 subgroup, which are closely related by protein sequence and comprise Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33. Recent evidence suggests that different TspanC8/ADAM10 complexes have distinct substrates and that ADAM10 should not be regarded as a single scissor, but as six different TspanC8/ADAM10 scissor complexes. This review discusses the published evidence for this “six scissor” hypothesis and the therapeutic potential this offers.

COVID 19 – Eye Issues

2020 ◽  
Vol 5 (Special) ◽  
Keyword(s):  
Host Cell ◽  
Target Cell ◽  
Cell Receptor ◽  
Human Tissues ◽  
Type Ii ◽  
Cell Infection ◽  
Host Cell Receptor ◽  
Infected Cells ◽  
Cellular Entry

The coronavirus illness (COVID-19) is caused by a new recombinant SARS-CoV (SARS-CoV) virus (SARS-CoV-2). Target cell infection by SARS-CoV is mediated by the prickly protein of the coronavirus and host cell receptor, enzyme 2 converting angiotensin (ACE2) [3]. Similarly, a recent study suggests that cellular entry by SARS-CoV-2 is dependent on both ACE2 as well as type II transmembrane axial protease (TMPRSS2) [4]. This means that detection of ACE2 and PRSS2 expression in human tissues can predict potential infected cells and their respective effects in COVID-19 patients [1].

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

scholarly journals The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

2021 ◽  
Vol 20 ◽  
pp. 232595822110090
Author(s):  
Kimberly K. Scarsi ◽  
Susan Swindells
Keyword(s):  
Medication Adherence ◽  
Antiretroviral Therapy ◽  
Hiv Treatment ◽  
Virologic Suppression ◽  
Social Barriers ◽  
Treatment And Prevention ◽  
Undetectable Viremia ◽  
Long Acting ◽  
Available Information ◽  
Living With Hiv

As with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers. Unfortunately, high levels of adherence to antiretroviral therapy are required to maintain virologic suppression. Alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products. Phase 3 data support the efficacy of nanoformulated injectable cabotegravir and rilpivirine for HIV treatment in patients with undetectable viremia, but we have yet to learn how this strategy may benefit those with medication adherence challenges. Despite this, the affected community and HIV providers are very interested in exploring the role of long-acting therapies to address some types of barriers to medication adherence. This review summarizes available information about the potential for long-acting therapy to improve adherence for some patients and outlines associated opportunities and challenges with the implementation of long-acting therapy for the treatment and prevention of HIV.

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