scholarly journals The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

2021 ◽  
pp. 100759
Author(s):  
Anthony J. Carlos ◽  
Dat P. Ha ◽  
Da-Wei Yeh ◽  
Richard Van Krieken ◽  
Chun-Chih Tseng ◽  
...  
Keyword(s):  
Viral Entry ◽  
Auxiliary Factor

scholarly journals GRP78 binds SARS-CoV-2 Spike protein and ACE2 and GRP78 depleting antibody blocks viral entry and infection in vitro

2021 ◽  
Author(s):  
Anthony J. Carlos ◽  
Dat P. Ha ◽  
Da-Wei Yeh ◽  
Richard Van Krieken ◽  
Parkash Gill ◽  
...  
Keyword(s):  
Cell Surface ◽  
Viral Entry ◽  
Lung Epithelial Cells ◽  
Spike Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Pandemic ◽  
Humanized Monoclonal Antibody ◽  
Important Host ◽  
Auxiliary Factor

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the current COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors may also play major roles in viral infection. Here we report that the stress-inducible molecular chaperone GRP78 can form a complex with the SARS-CoV-2 Spike protein and ACE2 intracellularly and on the cell surface, and that the substrate binding domain of GRP78 is critical for this function. Knock-down of GRP78 by siRNA dramatically reduced cell surface ACE2 expression. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159), selected for its ability to cause GRP78 endocytosis and its safe clinical profile in preclinical models, reduces cell surface ACE2 expression, SARS-CoV-2 Spike-driven viral entry, and significantly inhibits SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78.

Dissecting the Therapeutic Relevance of Gene Therapy in NeuroAIDS: An Evolving Epidemic

2020 ◽  
Vol 20 (3) ◽  
pp. 174-183
Author(s):  
Bushra Nabi ◽  
Saleha Rehman ◽  
Faheem Hyder Pottoo ◽  
Sanjula Baboota ◽  
Javed Ali
Keyword(s):  
Viral Entry ◽  
Due Process ◽  
Intrinsic Property ◽  
Antiretroviral Drugs ◽  
Viral Reservoir ◽  
Primary Concern ◽  
Cellular Delivery ◽  
Formidable Challenge ◽  
Neurological Conditions ◽  
The Brain

: NeuroAIDS, a disease incorporating both infectious and neurodegenerative pathways, is still a formidable challenge for the researchers to deal with. The primary concern for the treatment of neuroAIDS still remains the inaccessibility of the viral reservoir, making it indispensable for novel techniques to be continuously innovated. Since the brain serves as a reservoir for viral replication, it is pragmatic and a prerequisite to overcome the related barriers in order to improve the drug delivery to the brain. The current treatment ideology is based on the combinatorial approach of a mocktail of antiretroviral drugs. However, complete eradication of the disease could not be achieved. Thereby the arena of gene-based cellular delivery is trending and has created a niche for itself in the present scenario. To establish the supremacy of gene delivery, it is advisable to have a better understanding of the molecular mechanism involved in the due process. The mechanism associated with the activity of the anti-HIV gene lies in their intrinsic property to impart resistance to the HIV infection by targeting the viral entry channels. This review principally emphasizes on different types of gene therapies explored so far for the management of AIDS and its associated neurological conditions. Therefore it could rightly be said that we are at the crossroad where the need of the hour is to develop novel strategies for curbing AIDS and its associated neurological conditions.

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

2019 ◽  
Vol 19 (18) ◽  
pp. 1650-1675 ◽  
Author(s):  
Damoder Reddy Motati ◽  
Dilipkumar Uredi ◽  
E. Blake Watkins
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Biological Evaluation ◽  
New Drugs ◽  
Design Synthesis ◽  
Mortality And Morbidity ◽  
Glycoprotein Gp120 ◽  
Hiv Entry ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

A Potential Role of Coenzyme Q10 Deficiency in Severe SARS-CoV2 Infection

2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Vasilios M. Polymeropoulos ◽  
Keyword(s):  
Viral Entry ◽  
Coenzyme Q10 ◽  
Severe Infection ◽  
The Body ◽  
Therapeutic Options ◽  
Severe Illness ◽  
Infected People ◽  
Inflammatory State ◽  
Exogenous Compounds ◽  
Obesity Hypertension

There is a dramatic need for extensive research into the predictors of severe infection with SARS-CoV2 and therapeutic options for infected people. People who suffer from severe illness and higher mortality display a pattern of having specific co-morbidities (diabetes, obesity, hypertension) and are of higher age. Recent research has described methods of viral entry via receptors (ACE2, TMPRSS2) and the hyper-inflammatory state often associated with severe illness (increase in interleukins, increase in TNF-alpha). These discoveries have led to the research of currently available and developing therapies, that are helpful to patients. Deficiencies of specific vitamins and other endogenous molecules of the body should be examined to understand if a pattern exists among the people most severely affected. Coenzyme Q10 (CoQ10) is a fat-soluble substance ubiquitously expressed throughout the body that is important for the generation of ATP and mediation of inflammatory disease. CoQ10 faces a decline with increasing age, genetic predispositions, and ingestion of exogenous compounds that could reduce the level of CoQ10. Deficiencies and subsequent supplementation with CoQ10 recently has displayed encouraging results for the improvement of a wide variety of diseases. This manuscript is significant as it points to a potential relationship of CoQ10 and the population suffering from severe illness of COVID-19, and further encourages the need for research into measuring the levels of CoQ10 and vitamins to understand if levels predict severe illness and mortality. This could offer new avenues into research in combating this pandemic and potentially future therapeutic options.

SARS-CoV-2 Biology Insights, Part IV.Antibody-Dependent Enhancement (ADE) and the tricky “Herd Immunity”: narrative review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Whooping Cough ◽  
Common Knowledge ◽  
Herd Immunity ◽  
Life Quality ◽  
Host Cells ◽  
System P

BACKGROUND It is common knowledge that vaccination has improved our life quality and expectancy since it succeeded in achieving almost eradication of several diseases including chickenpox (varicella), diphtheria, hepatitis A and B, measles, meningococcal, mumps, pneumococcal, polio, rotavirus, rubella, tetanus and whooping cough (pertussis) Vaccination success is based on vaccine induction of neutralizing antibodies that help fight the infection (e.g. by a virus), preventing the disease. Conversely, Antibody-dependent enhancement (ADE) of a viral infection occurs when anti-viral antibodies facilitate viral entry into host cells and enhance viral infection in these cells. ADE has been previously studied in Dengue and HIV viruses and explains why a second infection with Dengue can be lethal. As already reviewed in Part I and Part II, SARS-Cov-2 shares with HIV not only 4 sequences in the Spike protein but also the capacity to attack the immune system. OBJECTIVE As HIV presents ADE, we wondered whether this was also the case regarding SARS-CoV-2. METHODS A literature review was done through Google. RESULTS SARS-CoV-2 presents ADE. As SARS, which does not have the 4 HIV-like inserts, has the same property, ADE would not be driven by the HIV-like spike sequences. CONCLUSIONS ADE can explain the failure of herd immunity-based strategies and will also probably hamper anti-SARS-CoV-2 vaccine development. As reviewed in Part I, there fortunately are promising therapeutic strategies for COVID-19, which should be further developed. In the meantime, complementary countermeasures to protect mainly the youth from this infection are presented to be discussed in Part V Viewpoint.

scholarly journals SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Dimitris G. Placantonakis ◽  
Maria Aguero-Rosenfeld ◽  
Abdallah Flaifel ◽  
John Colavito ◽  
Kenneth Inglima ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Viral Entry ◽  
Cell Types ◽  
Host Cells ◽  
Nasopharyngeal Swab ◽  
Rt Pcr ◽  
Neurologic Sequelae ◽  
Show Evidence ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.

scholarly journals ACE2, TMPRSS2 and L-SIGN expression in placentae from HIV-positive pregnancies exposed to antiretroviral therapy–implications for SARS-CoV-2 placental infection

2021 ◽  
Author(s):  
Smriti Kala ◽  
Ksenia Meteleva ◽  
Lena Serghides
Keyword(s):  
Antiretroviral Therapy ◽  
Pregnant Women ◽  
Viral Entry ◽  
Cell Entry ◽  
Hiv Positive ◽  
Mrna Levels ◽  
Black Race ◽  
Entry Receptor ◽  
Lower Expression ◽  
Human Placentae

Abstract Background SARS-CoV-2 binding receptor ACE2 and the spike protein priming protease TMPRSS2 are co-expressed in human placentae. It is unknown whether their expression is altered in the context of HIV infection and antiretroviral therapy (ART). Methods We compared mRNA levels of SARS-CoV-2 cell-entry mediators ACE2, TMPRSS2 and L-SIGN (an alternative entry receptor) by qPCR in 105 placentae: 45 from pregnant women with HIV (WHIV) exposed to protease inhibitor (PI)-based ART, 17 from WHIV on non-PI-based ART, and 43 from HIV-uninfected women. Results ACE2 levels were lower, while L-SIGN levels were higher in placentae from WHIV on PI-based ART as compared to those on non-PI-based ART and to HIV-uninfected women. TMPRSS2 levels were similar between groups. Black race was significantly associated with lower expression of ACE2 and higher expression of L-SIGN. ACE2 levels were significantly higher in placentae of female fetuses. Discussion We have identified pregnant women of Black race and WHIV who are on PI-based ART to have relatively lower expression of placental ACE2 than those of White race and HIV-uninfected women. This effect may potentially contribute to altered susceptibility to COVID-19 in these women, either favorably; by reduced viral entry, or detrimentally; by loss of ACE2 protection against hyperinflammation.

Sign in / Sign up

Export Citation Format

Share Document