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 Ivermectin for COVID-19: A broad-spectrum veterinary endectocide with antiviral activity

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Sharun Khan ◽  
Faslu Rahman C K ◽  
Jose Bosco ◽  
Irshad A ◽  
Dhama Kuldeep ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Therapeutic Potential ◽  
Natural Infection ◽  
Drug Repurposing ◽  
Importin Α ◽  
Parasitic Activity ◽  
Wonder Drug

Severe Acute Respiratory Syndrome coronavirus 2 (SARS CoV 2) is a novel zoonotic coronavirus that has emerged from Wuhan, China. Compared to its predecessors, Severe Acute Respiratory Syndrome CoV (SARS CoV) and Middle East Respiratory Syndrome CoV (MERS CoV), SARS CoV 2 has exhibited efficient human-to-human transmission. In addition to the efficient human-to-human transmission, SARS CoV 2 is also reported to infect other animal species such as cats, tigers, lions, dogs, and minks. The susceptibility of other felines such as cheetah, puma, jaguar, leopard, and lynx are unknown. The reports of SARS CoV 2 natural infection in animals opens up several opportunities to identify suitable animal models for the evaluation of SARS CoV 2 specific vaccines and therapeutics. Ivermectin is a macrocyclic lactone endectocide that has broad-spectrum anti-parasitic activity. The wonder drug ivermectin was also found to possess anti-viral, anti-bacterial, and anti-cancer activity. The antiviral activity exhibited by ivermectin against SARS CoV 2 is believed to be mediated via targeting the importin α/β-mediated nuclear transport and requires further validation. Since the antiviral activity of ivermectin is through a host-directed mechanism, it can reduce the viral load even if administered at a lower dose. Further studies are required to evaluate the efficacy of ivermectin based on in vivo as well as the clinical trials. Being an FDA approved antiparasitic drug, repurposing it for treating COVID-19 patients will be an easy task once it is found to have therapeutic potential.

scholarly journals Functional immune mapping with deep-learning enabled phenomics applied to immunomodulatory and COVID-19 drug discovery

2020 ◽  
Author(s):  
Michael F. Cuccarese ◽  
Berton A. Earnshaw ◽  
Katie Heiser ◽  
Ben Fogelson ◽  
Chadwick T. Davis ◽  
...  
Keyword(s):  
Deep Learning ◽  
Drug Discovery ◽  
High Throughput Screening ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Large Molecules ◽  
Tnf Α ◽  
Genetic Perturbations ◽  
Compound Screening ◽  
Model Drug

ABSTRACTDevelopment of accurate disease models and discovery of immune-modulating drugs is challenged by the immune system’s highly interconnected and context-dependent nature. Here we apply deep-learning-driven analysis of cellular morphology to develop a scalable “phenomics” platform and demonstrate its ability to identify dose-dependent, high-dimensional relationships among and between immunomodulators, toxins, pathogens, genetic perturbations, and small and large molecules at scale. High-throughput screening on this platform demonstrates rapid identification and triage of hits for TGF-β- and TNF-α-driven phenotypes. We deploy the platform to develop phenotypic models of active SARS-CoV-2 infection and of COVID-19-associated cytokine storm, surfacing compounds with demonstrated clinical benefit and identifying several new candidates for drug repurposing. The presented library of images, deep learning features, and compound screening data from immune profiling and COVID-19 screens serves as a deep resource for immune biology and cellular-model drug discovery with immediate impact on the COVID-19 pandemic.

scholarly journals Understanding Severe Acute Respiratory Syndrome Coronavirus 2 Replication to Design Efficient Drug Combination Therapies

Intervirology ◽  
2020 ◽  
Vol 63 (1-6) ◽  
pp. 2-9
Author(s):  
Joseph T. Ortega ◽  
Jose L. Zambrano ◽  
Beata Jastrzebska ◽  
Ferdinando Liprandi ◽  
Hector R. Rangel ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Infections ◽  
Therapeutic Targets ◽  
Drug Repurposing ◽  
Antiviral Effect ◽  
Cell Interaction ◽  
Combination Therapies ◽  
Early Stages ◽  
Antiviral Compounds ◽  
Viral Proteases

<b><i>Background:</i></b> The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease CO­VID-19 has strongly encouraged the search for antiviral compounds. Most of the evaluated drugs against SARS-CoV-2 derive from drug repurposing of Food and Drug Administration-approved molecules. These drugs have as target three major processes: (1) early stages of virus-cell interaction, (2) viral proteases, and (3) the viral RNA-dependent RNA polymerase. <b><i>Summary:</i></b> This review focused on the basic principles of virology and pharmacology to understand the importance of early stages of virus-cell interaction as therapeutic targets and other main processes vital for SARS-CoV-2 replication. Furthermore, we focused on describing the main targets associated with SARS-CoV-2 antiviral therapy and the rationale of drug combinations for efficiently suppressing viral replication. <b><i>Key Messages:</i></b> We hypothesized that blocking of both entry mechanisms could allow a more effective antiviral effect compared to the partial results obtained with chloroquine or its derivatives alone. This approach, already used to achieve an antiviral effect higher than that offered by every single drug administered separately, has been successfully applied in several viral infections such as HIV and HCV. This review will contribute to expanding the perception of the possible therapeutic targets in SARS-CoV-2 infection and highlight the benefits of using combination therapies.

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 Molnupiravir (EIDD-2801) inhibits SARS-CoV2 replication in Syrian hamsters model

2020 ◽  
Author(s):  
Rana Abdelnabi ◽  
Caroline S. Foo ◽  
Suzanne J. F. Kaptein ◽  
Xin Zhang ◽  
Lana Langendries ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antiviral Activity ◽  
Infectious Virus ◽  
Drug Repurposing ◽  
Antiviral Effect ◽  
Infection Model ◽  
Global Pandemic ◽  
Lung Histopathology ◽  
Model Treatment ◽  
Orally Bioavailable

Since its emergence in Wuhan, China in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide resulting in a global pandemic with >1.5 million deaths until now. In the search for small molecule inhibitors of SARS-CoV-2, drug repurposing is being extensively explored. Molnupiravir (EIDD-2801) is an orally bioavailable nucleoside analog that possesses a relatively broad-spectrum antiviral activity including against coronaviruses. We here studied the effect of EIDD-2801 in a well-established Syrian hamster SARS-CoV2 infection model. Treatment of SARS-CoV-2-infected hamsters with 200 mg/kg BID of EIDD-2801 for four consecutive days, starting from the day of infection, significantly reduced infectious virus titers and viral RNA loads in the lungs and markedly improved lung histopathology. When onset of treatment was delayed until 1 or 2 days after infection, a very modest antiviral effect was observed. The potential of EIDD-2801 for the treatment and or prevention of SARS-CoV2 deserves further attention.

Projecting the long-term benefits of single pill combination therapy for patients with hypertension in five countries

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Borghi ◽  
J.G Wang ◽  
A.V Rodionov ◽  
M Rosas ◽  
I.S Sohn ◽  
...  
Keyword(s):  
Combination Therapy ◽  
South Korea ◽  
Health Outcomes ◽  
Clinical Outcomes ◽  
Funding Source ◽  
Combination Therapies ◽  
Private Company ◽  
Treatment Pathways ◽  
Single Pill ◽  
The Impact

Abstract Background It is well established that single pill combination (SPC) therapies have the potential to improve patient adherence versus multi-pill regimens, thereby improving blood pressure control and clinical outcomes in populations with hypertension. Purpose To develop a microsimulation model, capturing different treatment pathways, to project the impact on clinical outcomes of using single pill combination therapies for the management of hypertension in five countries (Italy, Russia, China, South Korea and Mexico). Methods The model was designed to project health outcomes between 2020 and 2030 for populations with hypertension managed according to four different treatment pathways: current treatment practices [CTP], single drug with dosage titration first then sequential addition of other agents [start low and go slow, SLGS], free choice combination with multiple pills [FCC] and combination therapy in the form of a single pill [SPC]. Model inputs were derived from Global Burden of Disease 2017 dataset, including demographics, health status/risk factors, transition probabilities and treatment attributes/healthcare utilization, and the model incorporated real-world challenges to healthcare delivery such as access to care, SBP measurement error, adherence and therapeutic inertia. Simulated outcomes of mortality, incidence of chronic kidney disease (CKD), stroke and ischemic heart disease (IHD), and disability-adjusted life years (DALYs) due to these conditions were estimated for population of 1,000,000 simulated patients for each treatment pathway and country. Results SPC therapy was projected to improve health outcomes over SLGS, FCC and CTP over 10 years in all five countries. SPC was forecast to reduce mortality by 5.4% (Italy), 4.9% (Russia), 4.5% (China), 2.3% (South Korea) and 3.6% (Mexico) versus CTP and showed greater projected reductions in mortality than SLGS and FCC. DALYs were projected to be reduced with SPC therapy by between 5.7% (Italy) and 2.2% (South Korea) compared with CTP and reductions in the incidence of clinical events were also projected with SPC therapy, with decreases in the range of 11.5% (Italy) to 4.9% (South Korea) versus CTP. Conclusions Ten-year projections of clinical outcomes associated with different anti-hypertensive treatment pathways in five countries indicated that both combination therapies (FCC and SPC) are likely to reduce the disease burden of hypertension compared with conventional management approaches, with SPC showing the greatest overall benefits due to improved adherence. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi, Gentilly, France

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 Combination Regimens of Favipiravir Plus Interferon Alpha Inhibit Chikungunya Virus Replication in Clinically Relevant Human Cell Lines

2021 ◽  
Vol 9 (2) ◽  
pp. 307
Author(s):  
Evelyn J. Franco ◽  
Xun Tao ◽  
Kaley C. Hanrahan ◽  
Jieqiang Zhou ◽  
Jürgen B. Bulitta ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Cell Lines ◽  
Interferon Alpha ◽  
Chikungunya Virus ◽  
Plaque Assay ◽  
Human Infection ◽  
Viral Burden ◽  
Combination Regimens

Chikungunya virus (CHIKV) is an alphavirus associated with a broad tissue tropism for which no antivirals or vaccines are approved. This study evaluated the antiviral potential of favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) against CHIKV as mono- and combination-therapy in cell lines that are clinically relevant to human infection. Cells derived from human connective tissue (HT-1080), neurons (SK-N-MC), and skin (HFF-1) were infected with CHIKV and treated with different concentrations of FAV, IFN, or RBV. Viral supernatant was sampled daily and the burden was quantified by plaque assay on Vero cells. FAV and IFN were the most effective against CHIKV on various cell lines, suppressing the viral burden at clinically achievable concentrations; although the degree of antiviral activity was heavily influenced by cell type. RBV was not effective and demonstrated substantial toxicity, indicating that it is not a feasible candidate for CHIKV. The combination of FAV and IFN was then assessed on all cell lines. Combination therapy enhanced antiviral activity in HT-1080 and SK-N-MC cells, but not in HFF-1 cells. We developed a pharmacokinetic/pharmacodynamic model that described the viral burden and inhibitory antiviral effect. Simulations from this model predicted clinically relevant concentrations of FAV plus IFN completely suppressed CHIKV replication in HT-1080 cells, and considerably slowed down the rate of viral replication in SK-N-MC cells. The model predicted substantial inhibition of viral replication by clinical IFN regimens in HFF-1 cells. Our results highlight the antiviral potential of FAV and IFN combination regimens against CHIKV in clinically relevant cell types.

High-Throughput Screening to Identify Small Molecules That Selectively Inhibit APOL1 Protein Level in Podocytes

2021 ◽  
pp. 247255522110262
Author(s):  
Jonathan Choy ◽  
Yanqing Kan ◽  
Steve Cifelli ◽  
Josephine Johnson ◽  
Michelle Chen ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Screening Strategy ◽  
Time Resolved ◽  
Protein Levels ◽  
Increased Risk ◽  
Compound Screening ◽  
High Throughput Screens ◽  
Screening Library

High-throughput phenotypic screening is a key driver for the identification of novel chemical matter in drug discovery for challenging targets, especially for those with an unclear mechanism of pathology. For toxic or gain-of-function proteins, small-molecule suppressors are a targeting/therapeutic strategy that has been successfully applied. As with other high-throughput screens, the screening strategy and proper assays are critical for successfully identifying selective suppressors of the target of interest. We executed a small-molecule suppressor screen to identify compounds that specifically reduce apolipoprotein L1 (APOL1) protein levels, a genetically validated target associated with increased risk of chronic kidney disease. To enable this study, we developed homogeneous time-resolved fluorescence (HTRF) assays to measure intracellular APOL1 and apolipoprotein L2 (APOL2) protein levels and miniaturized them to 1536-well format. The APOL1 HTRF assay served as the primary assay, and the APOL2 and a commercially available p53 HTRF assay were applied as counterscreens. Cell viability was also measured with CellTiter-Glo to assess the cytotoxicity of compounds. From a 310,000-compound screening library, we identified 1490 confirmed primary hits with 12 different profiles. One hundred fifty-three hits selectively reduced APOL1 in 786-O, a renal cell adenocarcinoma cell line. Thirty-one of these selective suppressors also reduced APOL1 levels in conditionally immortalized human podocytes. The activity and specificity of seven resynthesized compounds were validated in both 786-O and podocytes.

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