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 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.

Computational Drug Repurposing: Current Trends

2019 ◽  
Vol 26 (28) ◽  
pp. 5389-5409 ◽  
Author(s):  
Berin Karaman ◽  
Wolfgang Sippl
Keyword(s):  
Systems Biology ◽  
Large Scale ◽  
Drug Repurposing ◽  
Protein Targets ◽  
Structure Information ◽  
Drug Candidates ◽  
Large Scale Data ◽  
Challenges And Opportunities ◽  
Disease Signatures ◽  
Novel Drug

: Biomedical discovery has been reshaped upon the exploding digitization of data which can be retrieved from a number of sources, ranging from clinical pharmacology to cheminformatics-driven databases. Now, supercomputing platforms and publicly available resources such as biological, physicochemical, and clinical data, can all be integrated to construct a detailed map of signaling pathways and drug mechanisms of action in relation to drug candidates. Recent advancements in computer-aided data mining have facilitated analyses of ‘big data’ approaches and the discovery of new indications for pre-existing drugs has been accelerated. Linking gene-phenotype associations to predict novel drug-disease signatures or incorporating molecular structure information of drugs and protein targets with other kinds of data derived from systems biology provide great potential to accelerate drug discovery and improve the success of drug repurposing attempts. In this review, we highlight commonly used computational drug repurposing strategies, including bioinformatics and cheminformatics tools, to integrate large-scale data emerging from the systems biology, and consider both the challenges and opportunities of using this approach. Moreover, we provide successful examples and case studies that combined various in silico drug-repurposing strategies to predict potential novel uses for known therapeutics.

Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents

2020 ◽  
Vol 17 (5) ◽  
pp. 716-724
Author(s):  
Yan A. Ivanenkov ◽  
Renat S. Yamidanov ◽  
Ilya A. Osterman ◽  
Petr V. Sergiev ◽  
Vladimir A. Aladinskiy ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Antibacterial Agents ◽  
Sos Response ◽  
Luciferase Assay ◽  
Translational Machinery ◽  
E Coli ◽  
New Class

Background: The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g. E. Coli, K. pneumoniae and S. aureus, have high resistance vs the last generations of cephalosporins, carbapenems and fluoroquinolones. During the past decades, only few successful efforts to develop and launch new antibacterial medications have been performed. This study aims to identify new class of antibacterial agents using novel high-throughput screening technique. Methods: We have designed library containing 125K compounds not similar in structure (Tanimoto coeff.< 0.7) to that published previously as antibiotics. The HTS platform based on double reporter system pDualrep2 was used to distinguish between molecules able to block translational machinery or induce SOS-response in a model E. coli system. MICs for most active chemicals in LB and M9 medium were determined using broth microdilution assay. Results: In an attempt to discover novel classes of antibacterials, we performed HTS of a large-scale small molecule library using our unique screening platform. This approach permitted us to quickly and robustly evaluate a lot of compounds as well as to determine the mechanism of action in the case of compounds being either translational machinery inhibitors or DNA-damaging agents/replication blockers. HTS has resulted in several new structural classes of molecules exhibiting an attractive antibacterial activity. Herein, we report as promising antibacterials. Two most active compounds from this series showed MIC value of 1.2 (5) and 1.8 μg/mL (6) and good selectivity index. Compound 6 caused RFP induction and low SOS response. In vitro luciferase assay has revealed that it is able to slightly inhibit protein biosynthesis. Compound 5 was tested on several archival strains and exhibited slight activity against gram-negative bacteria and outstanding activity against S. aureus. The key structural requirements for antibacterial potency were also explored. We found, that the unsubstituted carboxylic group is crucial for antibacterial activity as well as the presence of bulky hydrophobic substituents at phenyl fragment. Conclusion: The obtained results provide a solid background for further characterization of the 5'- (carbonylamino)-2,3'-bithiophene-4'-carboxylate derivatives discussed herein as new class of antibacterials and their optimization campaign.

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 Rapid Spread of the SARS-CoV-2 Variant of Concern 202012/01 in Southern Italy (December 2020–March 2021)

2021 ◽  
Vol 18 (9) ◽  
pp. 4766
Author(s):  
Daniela Loconsole ◽  
Francesca Centrone ◽  
Caterina Morcavallo ◽  
Silvia Campanella ◽  
Anna Sallustio ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Large Scale ◽  
Southern Italy ◽  
Whole Genome ◽  
Third Wave ◽  
Gene Target ◽  
The Third ◽  
Rapid Spread ◽  
Pharmaceutical Interventions ◽  
Over Time

Epidemiological and virological studies have revealed that SARS-CoV-2 variants of concern (VOCs) are emerging globally, including in Europe. The aim of this study was to evaluate the spread of B.1.1.7-lineage SARS-CoV-2 in southern Italy from December 2020–March 2021 through the detection of the S gene target failure (SGTF), which could be considered a robust proxy of VOC B.1.1.7. SGTF was assessed on 3075 samples from week 52/2020 to week 10/2021. A subset of positive samples identified in the Apulia region during the study period was subjected to whole-genome sequencing (WGS). A descriptive and statistical analysis of the demographic and clinical characteristics of cases according to SGTF status was performed. Overall, 20.2% of samples showed SGTF; 155 strains were confirmed as VOC 202012/01 by WGS. The proportion of SGTF-positive samples rapidly increased over time, reaching 69.2% in week 10/2021. SGTF-positive cases were more likely to be symptomatic and to result in hospitalization (p < 0.0001). Despite the implementation of large-scale non-pharmaceutical interventions (NPIs), such as the closure of schools and local lockdowns, a rapid spread of VOC 202012/01 was observed in southern Italy. Strengthened NPIs and rapid vaccine deployment, first among priority groups and then among the general population, are crucial both to contain the spread of VOC 202012/01 and to flatten the curve of the third wave.

scholarly journals Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1170 ◽  
Author(s):  
Emily S. Mathews ◽  
Audrey R. Odom John
Keyword(s):  
Drug Resistance ◽  
Malaria Elimination ◽  
Large Scale ◽  
Therapeutic Targets ◽  
Control Measures ◽  
Multi Drug Resistance ◽  
Development Projects ◽  
Combination Therapies ◽  
The Past ◽  
Antimalarial Compounds

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination.

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