scholarly journals A Graph Convolutional Network-based screening strategy for rapid identification of SARS-CoV-2 cell-entry inhibitors

2021 ◽  
Author(s):  
Peng Gao ◽  
Miao Xu ◽  
Qi Zhang ◽  
Catherine Chen ◽  
Hui Guo ◽  
...  
Keyword(s):  
Drug Targets ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Screening Strategy ◽  
Cell Entry ◽  
Classification Model ◽  
Convolutional Network ◽  
Entry Inhibitors ◽  
Drug Identification ◽  
Conventional Drug

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time-consuming and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in ~2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets.

scholarly journals Screening a library of FDA-approved and bioactive compounds for antiviral activity against SARS-CoV-2

2020 ◽  
Author(s):  
Scott B. Biering ◽  
Erik Van Dis ◽  
Eddie Wehri ◽  
Livia H. Yamashiro ◽  
Xammy Nguyenla ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Combination Therapy ◽  
Global Health ◽  
Antiviral Activity ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Screening Strategy ◽  
Combination Therapies ◽  
Pulmonary Epithelial Cells ◽  
Compound Screening

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 80 million cases and 1.7 million deaths to date while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent antiviral activity across multiple orthogonal assays. Hits include known antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as kinases and proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with remdesivir, the only antiviral approved by the FDA to treat COVID-19, highlighting the potential for combination therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective antiviral mono- or combination therapies to treat COVID-19.

scholarly journals Clinically Approved Ion Channel Inhibitors Close Gates for Hepatitis C Virus and Open Doors for Drug Repurposing in Infectious Viral Diseases

2016 ◽  
Vol 91 (2) ◽  
Author(s):  
Thomas Pietschmann
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Cell Entry ◽  
Severe Liver ◽  
Entry Inhibitors ◽  
Chronic Hepatitis C Virus ◽  
Severe Liver Disease ◽  
Limit Access

ABSTRACT Chronic hepatitis C virus (HCV) infection causes severe liver disease and affects ca. 146 million individuals. Novel directly acting antivirals targeting HCV have revolutionized treatment. However, high costs limit access to therapy. Recently, several related drugs used in humans to treat allergies or as neuroleptics emerged as potent HCV cell entry inhibitors. Insights into their antiviral modes of action may increase opportunities for drug repurposing in hepatitis C and possibly other important human viral infections.

scholarly journals Identifying SARS-CoV-2 entry inhibitors through drug repurposing screens of SARS-S and MERS-S pseudotyped particles

2020 ◽  
Author(s):  
Catherine Z. Chen ◽  
Miao Xu ◽  
Manisha Pradhan ◽  
Kirill Gorshkov ◽  
Jennifer Petersen ◽  
...  
Keyword(s):  
High Throughput ◽  
Broad Spectrum ◽  
Vaccine Development ◽  
Drug Repurposing ◽  
Cell Entry ◽  
Entry Inhibitors ◽  
Small Molecule Drugs ◽  
Global Pandemic ◽  
Initial Stage ◽  
Approved Drugs

AbstractWhile vaccine development will hopefully quell the global pandemic of COVID-19 caused by SARS-CoV-2, small molecule drugs that can effectively control SARS-CoV-2 infection are urgently needed. Here, inhibitors of spike (S) mediated cell entry were identified in a high throughput screen of an approved drugs library with SARS-S and MERS-S pseudotyped particle entry assays. We discovered six compounds (cepharanthine, abemaciclib, osimertinib, trimipramine, colforsin, and ingenol) to be broad spectrum inhibitors for spike-mediated entry. This work should contribute to the development of effective treatments against the initial stage of viral infection, thus reducing viral burden in COVID-19 patients.Abstract Figure

Systematic Design and Evaluation of Drug Repurposing-Oriented Alzheimer’s Disease Ontology (Preprint)

2020 ◽  
Author(s):  
Fang Li ◽  
Muhammad "Tuan" Amith ◽  
Grace Xiong ◽  
Jingcheng Du ◽  
Yang Xiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Drug Repurposing ◽  
Essential Elements ◽  
Genomic Research ◽  
Core Knowledge ◽  
Disease Ontology ◽  
Hybrid Strategy ◽  
Complementary Strategy

BACKGROUND Alzheimer’s Disease (AD) is a devastating neurodegenerative disease, of which the pathophysiology is insufficiently understood, and the curative drugs are long-awaited to be developed. Computational drug repurposing introduces a promising complementary strategy of drug discovery, which benefits from an accelerated development process and decreased failure rate. However, generating new hypotheses in AD drug repurposing requires multi-dimensional and multi-disciplinary data integration and connection, posing a great challenge in the era of big data. By integrating data with computable semantics, ontologies could infer unknown relationships through automated reasoning and fulfill an essential role in supporting computational drug repurposing. OBJECTIVE The study aimed to systematically design a robust Drug Repurposing-Oriented Alzheimer’s Disease Ontology (DROADO), which could model fundamental elements and their relationships involved in AD drug repurposing and integrate their up-to-date research advance comprehensively. METHODS We devised a core knowledge model of computational AD drug repurposing, based on both pre-genomic and post-genomic research paradigms. The model centered on the possible AD pathophysiology and abstracted the essential elements and their relationships. We adopted a hybrid strategy to populate the ontology (classes and properties), including importing from well-curated databases, extracting from high-quality papers and reusing the existing ontologies. We also leveraged n-ary relations and nanopublication graphs to enrich the object relations, making the knowledge stored in the ontology more powerful in supporting computational processing. The initially built ontology was evaluated by a semiotic-driven and web-based tool Ontokeeper. RESULTS The current version of DROADO was composed of 1,021 classes, 23 object properties and 3,207 axioms, depicting a fundamental network related to computational neuroscience concepts and relationships. Assessment using semiotic evaluation metrics by OntoKeeper indicated sufficient preliminary quality (semantics, usefulness and community-consensus) of the ontology. CONCLUSIONS As an in-depth knowledge base, DROADO would be promising in enabling computational algorithms to realize supervised mining from multi-source data, and ultimately, facilitating the discovery of novel AD drug targets and the realization of AD drug repurposing.

scholarly journals Genomics-driven drug discovery based on disease-susceptibility genes

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Kyuto Sonehara ◽  
Yukinori Okada
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Disease Susceptibility ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Drug Repurposing ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Disease Associations

AbstractGenome-wide association studies have identified numerous disease-susceptibility genes. As knowledge of gene–disease associations accumulates, it is becoming increasingly important to translate this knowledge into clinical practice. This challenge involves finding effective drug targets and estimating their potential side effects, which often results in failure of promising clinical trials. Here, we review recent advances and future perspectives in genetics-led drug discovery, with a focus on drug repurposing, Mendelian randomization, and the use of multifaceted omics data.

scholarly journals Rapid discovery of self-assembling peptides with one-bead one-compound peptide library

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pei-Pei Yang ◽  
Yi-Jing Li ◽  
Yan Cao ◽  
Lu Zhang ◽  
Jia-Qi Wang ◽  
...  
Keyword(s):  
Combinatorial Library ◽  
Rapid Identification ◽  
Screening Strategy ◽  
Peptide Library ◽  
Aqueous Environment ◽  
Self Assembling ◽  
Material Sciences ◽  
The One ◽  
Combinatorial Space ◽  
Simple Screening

AbstractSelf-assembling peptides have shown tremendous potential in the fields of material sciences, nanoscience, and medicine. Because of the vast combinatorial space of even short peptides, identification of self-assembling sequences remains a challenge. Herein, we develop an experimental method to rapidly screen a huge array of peptide sequences for self-assembling property, using the one-bead one-compound (OBOC) combinatorial library method. In this approach, peptides on beads are N-terminally capped with nitro-1,2,3-benzoxadiazole, a hydrophobicity-sensitive fluorescence molecule. Beads displaying self-assembling peptides would fluoresce under aqueous environment. Using this approach, we identify eight pentapeptides, all of which are able to self-assemble into nanoparticles or nanofibers. Some of them are able to interact with and are taken up efficiently by HeLa cells. Intracellular distribution varied among these non-toxic peptidic nanoparticles. This simple screening strategy has enabled rapid identification of self-assembling peptides suitable for the development of nanostructures for various biomedical and material applications.

scholarly journals Mammalian deubiquitinating enzyme inhibitors display in vitro and in vivo activity against malaria parasites and potentiate artemisinin action

2020 ◽  
Author(s):  
Nelson V. Simwela ◽  
Katie R. Hughes ◽  
Michael T. Rennie ◽  
Michael P. Barrett ◽  
Andrew P. Waters
Keyword(s):  
Anticancer Agents ◽  
Drug Targets ◽  
Reverse Genetics ◽  
Enzyme Inhibitors ◽  
Artemisinin Resistance ◽  
Drug Repurposing ◽  
Antimalarial Drugs ◽  
Malaria Parasites

AbstractCurrent malaria control efforts rely significantly on artemisinin combinational therapies which have played massive roles in alleviating the global burden of the disease. Emergence of resistance to artemisinins is therefore, not just alarming but requires immediate intervention points such as development of new antimalarial drugs or improvement of the current drugs through adjuvant or combination therapies. Artemisinin resistance is primarily conferred by Kelch13 propeller mutations which are phenotypically characterised by generalised growth quiescence, altered haemoglobin trafficking and downstream enhanced activity of the parasite stress pathways through the ubiquitin proteasome system (UPS). Previous work on artemisinin resistance selection in a rodent model of malaria, which we and others have recently validated using reverse genetics, has also shown that mutations in deubiquitinating enzymes, DUBs (upstream UPS component) modulates susceptibility of malaria parasites to both artemisinin and chloroquine. The UPS or upstream protein trafficking pathways have, therefore, been proposed to be not just potential drug targets, but also possible intervention points to overcome artemisinin resistance. Here we report the activity of small molecule inhibitors targeting mammalian DUBs in malaria parasites. We show that generic DUB inhibitors can block intraerythrocytic development of malaria parasites in vitro and possess antiparasitic activity in vivo and can be used in combination with additive effect. We also show that inhibition of these upstream components of the UPS can potentiate the activity of artemisinin in vitro as well as in vivo to the extent that ART resistance can be overcome. Combinations of DUB inhibitors anticipated to target different DUB activities and downstream 20s proteasome inhibitors are even more effective at improving the potency of artemisinins than either inhibitors alone providing proof that targeting multiple UPS activities simultaneously could be an attractive approach to overcoming artemisinin resistance. These data further validate the parasite UPS as a target to both enhance artemisinin action and potentially overcome resistance. Lastly, we confirm that DUB inhibitors can be developed into in vivo antimalarial drugs with promise for activity against all of human malaria and could thus further exploit their current pursuit as anticancer agents in rapid drug repurposing programs.Graphical abstract

scholarly journals Characterization of SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 on cell entry, host range, and sensitivity to convalescent plasma and ACE2 decoy receptor

2021 ◽  
Author(s):  
Wenlin Ren ◽  
Xiaohui Ju ◽  
Mingli Gong ◽  
Jun Lan ◽  
Yanying Yu ◽  
...  
Keyword(s):  
Host Range ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Cell Entry ◽  
Decoy Receptor ◽  
Host Tropism ◽  
Entry Inhibitors ◽  
Rapid Spread ◽  
Entry Efficiency

ABSTRACTRecently, highly transmissible SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 were identified in India with mutations within the spike proteins. The spike protein of Kappa contains four mutations E154K, L452R, E484Q and P681R, and Delta contains L452R, T478K and P681R, while B.1.618 spike harbors mutations Δ145-146 and E484K. However, it remains unknown whether these variants have altered in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies as well as entry inhibitors. In this study, we found that Kappa, Delta or B.1.618 spike uses human ACE2 with no or slightly increased efficiency, while gains a significantly increased binding affinity with mouse, marmoset and koala ACE2 orthologs, which exhibits limited binding with WT spike. Furthermore, the P618R mutation leads to enhanced spike cleavage, which could facilitate viral entry. In addition, Kappa, Delta and B.1.618 exhibits a reduced sensitivity to neutralization by convalescent sera owning to the mutation of E484Q, T478K, Δ145-146 or E484K, but remains sensitive to entry inhibitors-ACE2-lg decoy receptor. Collectively, our study revealed that enhanced human and mouse ACE2 receptor engagement, increased spike cleavage and reduced sensitivity to neutralization antibodies of Kappa, Delta and B.1.618 may contribute to the rapid spread of these variants and expanded host range. Furthermore, our result also highlighted that ACE2-lg could be developed as broad-spectrum antiviral strategy against SARS-CoV-2 variants.

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