scholarly journals Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates

2022 ◽  
Author(s):  
Denisa Bojkova ◽  
Marek Widera ◽  
Sandra Ciesek ◽  
Mark N Wass ◽  
Martin Michaelis ◽  
...  
Keyword(s):  
Host Cell ◽  
Active Compound ◽  
Drug Sensitivity ◽  
Antiviral Agents ◽  
Mechanistic Explanation ◽  
Interferon Response ◽  
Clinical Testing ◽  
Drug Candidates ◽  
Similar Drug ◽  
Interferon Antagonism

The SARS-CoV-2 Omicron variant is currently causing a large number of infections in many countries. A number of antiviral agents are approved or in clinical testing for the treatment of COVID-19. Despite the high number of mutations in the Omicron variant, we here show that Omicron isolates display similar sensitivity to eight of the most important anti-SARS-CoV-2 drugs and drug candidates (including remdesivir, molnupiravir, and PF-07321332, the active compound in paxlovid), which is of timely relevance for the treatment of the increasing number of Omicron patients. Most importantly, we also found that the Omicron variant displays a reduced capability of antagonising the host cell interferon response. This provides a potential mechanistic explanation for the clinically observed reduced pathogenicity of Omicron variant viruses compared to Delta variant viruses.

scholarly journals Large Scale Profiling of SARS-CoV-2-Infected Patients Identified Potential Therapeutic Host Targets and Drug Candidates for COVID-19

2021 ◽  
Author(s):  
Sidharth Jain ◽  
Samantha Rego ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
Host Cell ◽  
Large Scale ◽  
Therapeutic Targets ◽  
Interferon Response ◽  
Translational Machinery ◽  
Drug Candidates ◽  
Rapid Spread ◽  
Key Genes ◽  
Gene Expression Alterations ◽  
Disease Signatures

Given the rapid spread of SARS-CoV-2 and rising death toll of COVID-19 in the current absence of effective treatments, it is imperative that therapeutics are developed and made available to patients as quickly as possible. Publicly available COVID-19 patient data can be used to identify host therapeutic targets, tailoring treatments to the disease signatures observed in patients. In this study, we identify potential host therapeutic targets based on gene expression alterations observed in COVID-19 patients. We analyzed RNAseq data from airway samples of COVID-19 patients and healthy controls to detect significantly differentially expressed genes and pathways that present potential therapeutic targets. Our analysis revealed expression changes in key genes involved in activation of immune pathways, as well as genes targeted by SARS-CoV2 to interfere with normal host cell functioning. Critical changes were observed in a number of genes, including EIF2AK2, which was shown to play important roles in activating the interferon response and interfering with host cell translational machinery in SARS-CoV-2 infection, presenting a prospective therapeutic target. We also identified drugs with potential to modulate multiple therapeutic targets within the most significant pathways. Our results both validate key genes, pathways, and drug candidates that have been reported by other studies and suggest others that have not been well-characterized and warrant further investigation by future studies. Further investigation of these therapeutic targets and their drug interactions may lead to effective therapeutic strategies to combat the current COVID-19 pandemic and protect against future outbreaks.<br>

scholarly journals Large Scale Profiling of SARS-CoV-2-Infected Patients Identified Potential Therapeutic Host Targets and Drug Candidates for COVID-19

2021 ◽  
Author(s):  
Sidharth Jain ◽  
Samantha Rego ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
Host Cell ◽  
Large Scale ◽  
Therapeutic Targets ◽  
Interferon Response ◽  
Translational Machinery ◽  
Drug Candidates ◽  
Rapid Spread ◽  
Key Genes ◽  
Gene Expression Alterations ◽  
Disease Signatures

Given the rapid spread of SARS-CoV-2 and rising death toll of COVID-19 in the current absence of effective treatments, it is imperative that therapeutics are developed and made available to patients as quickly as possible. Publicly available COVID-19 patient data can be used to identify host therapeutic targets, tailoring treatments to the disease signatures observed in patients. In this study, we identify potential host therapeutic targets based on gene expression alterations observed in COVID-19 patients. We analyzed RNAseq data from airway samples of COVID-19 patients and healthy controls to detect significantly differentially expressed genes and pathways that present potential therapeutic targets. Our analysis revealed expression changes in key genes involved in activation of immune pathways, as well as genes targeted by SARS-CoV2 to interfere with normal host cell functioning. Critical changes were observed in a number of genes, including EIF2AK2, which was shown to play important roles in activating the interferon response and interfering with host cell translational machinery in SARS-CoV-2 infection, presenting a prospective therapeutic target. We also identified drugs with potential to modulate multiple therapeutic targets within the most significant pathways. Our results both validate key genes, pathways, and drug candidates that have been reported by other studies and suggest others that have not been well-characterized and warrant further investigation by future studies. Further investigation of these therapeutic targets and their drug interactions may lead to effective therapeutic strategies to combat the current COVID-19 pandemic and protect against future outbreaks.<br>

scholarly journals Large Scale Profiling of SARS-CoV-2-Infected Patients Identified Potential Therapeutic Host Targets and Drug Candidates for COVID-19

2021 ◽  
Author(s):  
Sidharth Jain ◽  
Samantha Rego ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
Host Cell ◽  
Large Scale ◽  
Therapeutic Targets ◽  
Interferon Response ◽  
Translational Machinery ◽  
Drug Candidates ◽  
Rapid Spread ◽  
Key Genes ◽  
Gene Expression Alterations ◽  
Disease Signatures

Given the rapid spread of SARS-CoV-2 and rising death toll of COVID-19 in the current absence of effective treatments, it is imperative that therapeutics are developed and made available to patients as quickly as possible. Publicly available COVID-19 patient data can be used to identify host therapeutic targets, tailoring treatments to the disease signatures observed in patients. In this study, we identify potential host therapeutic targets based on gene expression alterations observed in COVID-19 patients. We analyzed RNAseq data from airway samples of COVID-19 patients and healthy controls to detect significantly differentially expressed genes and pathways that present potential therapeutic targets. Our analysis revealed expression changes in key genes involved in activation of immune pathways, as well as genes targeted by SARS-CoV2 to interfere with normal host cell functioning. Critical changes were observed in a number of genes, including EIF2AK2, which was shown to play important roles in activating the interferon response and interfering with host cell translational machinery in SARS-CoV-2 infection, presenting a prospective therapeutic target. We also identified drugs with potential to modulate multiple therapeutic targets within the most significant pathways. Our results both validate key genes, pathways, and drug candidates that have been reported by other studies and suggest others that have not been well-characterized and warrant further investigation by future studies. Further investigation of these therapeutic targets and their drug interactions may lead to effective therapeutic strategies to combat the current COVID-19 pandemic and protect against future outbreaks.<br>

scholarly journals Large Scale Profiling of SARS-CoV-2-Infected Patients Identified Potential Therapeutic Host Targets and Drug Candidates for COVID-19

2021 ◽  
Author(s):  
Sidharth Jain ◽  
Samantha Rego ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
Host Cell ◽  
Large Scale ◽  
Therapeutic Targets ◽  
Interferon Response ◽  
Translational Machinery ◽  
Drug Candidates ◽  
Rapid Spread ◽  
Key Genes ◽  
Gene Expression Alterations ◽  
Disease Signatures

Given the rapid spread of SARS-CoV-2 and rising death toll of COVID-19 in the current absence of effective treatments, it is imperative that therapeutics are developed and made available to patients as quickly as possible. Publicly available COVID-19 patient data can be used to identify host therapeutic targets, tailoring treatments to the disease signatures observed in patients. In this study, we identify potential host therapeutic targets based on gene expression alterations observed in COVID-19 patients. We analyzed RNAseq data from airway samples of COVID-19 patients and healthy controls to detect significantly differentially expressed genes and pathways that present potential therapeutic targets. Our analysis revealed expression changes in key genes involved in activation of immune pathways, as well as genes targeted by SARS-CoV2 to interfere with normal host cell functioning. Critical changes were observed in a number of genes, including EIF2AK2, which was shown to play important roles in activating the interferon response and interfering with host cell translational machinery in SARS-CoV-2 infection, presenting a prospective therapeutic target. We also identified drugs with potential to modulate multiple therapeutic targets within the most significant pathways. Our results both validate key genes, pathways, and drug candidates that have been reported by other studies and suggest others that have not been well-characterized and warrant further investigation by future studies. Further investigation of these therapeutic targets and their drug interactions may lead to effective therapeutic strategies to combat the current COVID-19 pandemic and protect against future outbreaks.<br>

scholarly journals Modulation of Autophagy by SARS-CoV-2: A Potential Threat for Cardiovascular System

2020 ◽  
Vol 11 ◽  
Author(s):  
Puneet Kaur Randhawa ◽  
Kaylyn Scanlon ◽  
Jay Rappaport ◽  
Manish K. Gupta
Keyword(s):  
Host Cell ◽  
Rna Virus ◽  
Clinical Manifestations ◽  
Cardiovascular Complications ◽  
Extracellular Proteases ◽  
Potential Threat ◽  
Surface Receptors ◽  
Drug Candidates ◽  
A Genome ◽  
Number Of Patients

Recently, we have witnessed an unprecedented increase in the number of patients suffering from respiratory tract illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 virus is a single-stranded positive-sense RNA virus with a genome size of ~29.9 kb. It is believed that the viral spike (S) protein attaches to angiotensin converting enzyme 2 cell surface receptors and, eventually, the virus gains access into the host cell with the help of intracellular/extracellular proteases or by the endosomal pathway. Once, the virus enters the host cell, it can either be degraded via autophagy or evade autophagic degradation and replicate using the virus encoded RNA dependent RNA polymerase. The virus is highly contagious and can impair the respiratory system of the host causing dyspnea, cough, fever, and tightness in the chest. This disease is also characterized by an abrupt upsurge in the levels of proinflammatory/inflammatory cytokines and chemotactic factors in a process known as cytokine storm. Certain reports have suggested that COVID-19 infection can aggravate cardiovascular complications, in fact, the individuals with underlying co-morbidities are more prone to the disease. In this review, we shall discuss the pathogenesis, clinical manifestations, potential drug candidates, the interaction between virus and autophagy, and the role of coronavirus in exaggerating cardiovascular complications.

scholarly journals Thermo-Analytical and Compatibility Study with Mechanistic Explanation of Degradation Kinetics of Ambroxol Hydrochloride Tablets under Non-Isothermal Conditions

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1910
Author(s):  
Dijana Jelić ◽  
Snežana Papović ◽  
Milan Vraneš ◽  
Slobodan Gadžurić ◽  
Silvia Berto ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Active Compound ◽  
Degradation Kinetics ◽  
Practical Interest ◽  
Mechanistic Explanation ◽  
Compatibility Study ◽  
Order Kinetic ◽  
Order Kinetic Model ◽  
Synthetic Derivative ◽  
Ambroxol Hydrochloride

Ambroxol hydrochloride (AMB), used as a broncho secretolytic and an expectorant drug, is a semi-synthetic derivative of vasicine obtained from the Indian shrub Adhatoda vasica. It is a metabolic product of bromhexine. The paper provides comprehensive and detailed research on ambroxol hydrochloride, gives information on thermal stability, the mechanism of AMB degradation, and data of practical interest for optimization of formulation that contains AMB as an active compound. Investigation on pure AMB and in commercial formulation Flavamed® tablet (FT), which contains AMB as an active compound, was performed systematically using thermal and spectroscopic methods, along with a sophisticated and practical statistical approach. AMB proved to be a heat-stable and humidity-sensitive drug. For its successful formulation, special attention should be addressed to excipients since it was found that polyvinyl pyrrolidone and Mg stearate affect the thermal stability of AMB. At the same time, lactose monohydrate contributes to faster degradation of AMB and change in decomposition mechanism. It was found that the n-th order kinetic model mechanistically best describes the decomposition process of pure AMB and in Flavamed® tablets.

scholarly journals Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus

2016 ◽  
Vol 60 (6) ◽  
pp. 3786-3793 ◽  
Author(s):  
Isabel Gallego ◽  
Julie Sheldon ◽  
Elena Moreno ◽  
Josep Gregori ◽  
Josep Quer ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Sensitivity ◽  
Specific Resistance ◽  
Antiviral Agents ◽  
Resistance Mutations ◽  
Coding Region ◽  
High Fitness ◽  
Selection Of

Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct-acting antiviral agents such as telaprevir or daclatasvir, but fitness-dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low- and high-fitness HCV populations and biological clones derived from them were used to infect Huh-7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B-coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high-fitness HCV populations, without the acquisition of sofosbuvir-specific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high-fitness individual biological clones. In independently derived high-fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir-specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness-dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvir-specific resistance mutations, linked toin vivofitness of pretreatment viral populations.

scholarly journals The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States

2020 ◽  
Author(s):  
Pasquale Laise ◽  
Gideon Bosker ◽  
Xiaoyun Sun ◽  
Yao Shen ◽  
Eugene F. Douglass ◽  
...  
Keyword(s):  
Host Cell ◽  
Antiviral Agents ◽  
Host Cells ◽  
Master Regulator ◽  
Viral Pathogens ◽  
Host Cell Proteins ◽  
Adenocarcinoma Cells ◽  
Efficient Replication ◽  
Specific Proteins ◽  
Transcriptional State

Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins—whose aberrant activities govern the reprogramed state of infected-coronavirus cells—presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to established treatments. Specifically, we propose that a small module of host cell Master Regulator proteins (ViroCheckpoint) is hijacked by the virus to support its efficient replication and release. Conventional methodologies are not well suited to elucidate these potentially targetable proteins. By using the VIPER network-based algorithm, we successfully interrogated 12h, 24h, and 48h signatures from Calu-3 lung adenocarcinoma cells infected with SARS-CoV, to elucidate the time-dependent reprogramming of host cells and associated Master Regulator proteins. We used the NYS CLIA-certified Darwin OncoTreat algorithm, with an existing database of RNASeq profiles following cell perturbation with 133 FDA-approved and 195 late-stage experimental compounds, to identify drugs capable of virtually abrogating the virus-induced Master Regulator signature. This approach to drug prioritization and repurposing can be trivially extended to other viral pathogens, including SARS-CoV-2, as soon as the relevant infection signature becomes available.

scholarly journals How Many Mammalian Reovirus Proteins are involved in the Control of the Interferon Response?

Pathogens ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 83 ◽  
Author(s):  
Delphine Lanoie ◽  
Simon Boudreault ◽  
Martin Bisaillon ◽  
Guy Lemay
Keyword(s):  
Immune Response ◽  
Host Cell ◽  
Innate Immune Response ◽  
Resistance Mechanisms ◽  
Innate Immune ◽  
Interferon Response ◽  
Gene Products ◽  
Interferon Signaling ◽  
Host Cell Response ◽  
Response Network

As with most viruses, mammalian reovirus can be recognized and attacked by the host-cell interferon response network. Similarly, many viruses have developed resistance mechanisms to counteract the host-cell response at different points of this response. Reflecting the complexity of the interferon signaling pathways as well as the resulting antiviral response, viruses can—and often have—evolved many determinants to interfere with this innate immune response and allow viral replication. In the last few years, it has been evidenced that mammalian reovirus encodes many different determinants that are involved in regulating the induction of the interferon response or in interfering with the action of interferon-stimulated gene products. In this brief review, we present our current understanding of the different reovirus proteins known to be involved, introduce their postulated modes of action, and raise current questions that may lead to further investigations.

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