Blockade of SARS-CoV-2 infection in vitro by highly potent PI3K-α/mTOR/BRD4 inhibitor

Acharya, Arpan; Pandey, Kabita; Thurman, Michellie; Challagundala, Kishore B; Vann, Kendra R.; Kutateladze, Tatiana G.; Morales, Guillermo; Durden, Donald L.; Byrareddy, Siddappa N.

doi:10.1101/2021.03.02.433604

Cited by 14 publications

(11 citation statements)

References 62 publications

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“…expressed 26 SARS‐CoV‐2 proteins in human cells, which were used for affinity‐purification MS; this study identified 332 high‐confidence protein–protein interactions between SARS‐CoV‐2 and human proteins, and more than 66 of 332 proteins were identified as druggable targets. Based on this work, Acharya et al 206 . demonstrated that BRD2 is a potential target for development of therapeutics against SARS‐CoV‐2 in vitro.…”

Section: Application Of Proteomics In the Emerging Pandemicmentioning

confidence: 82%

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Application of omics technology to combat the COVID‐19 pandemic

Yang

Yan²,

Zhong³

2021

MedComm

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As of August 27, 2021, the ongoing pandemic of coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread to over 220 countries, areas, and territories. Thus far, 214,468,601 confirmed cases, including 4,470,969 deaths, have been reported to the World Health Organization. To combat the COVID‐19 pandemic, multiomics‐based strategies, including genomics, transcriptomics, proteomics, and metabolomics, have been used to study the diagnosis methods, pathogenesis, prognosis, and potential drug targets of COVID‐19. In order to help researchers and clinicians to keep up with the knowledge of COVID‐19, we summarized the most recent progresses reported in omics‐based research papers. This review discusses omics‐based approaches for studying COVID‐19, summarizing newly emerged SARS‐CoV‐2 variants as well as potential diagnostic methods, risk factors, and pathological features of COVID‐19. This review can help researchers and clinicians gain insight into COVID‐19 features, providing direction for future drug development and guidance for clinical treatment, so that patients can receive appropriate treatment as soon as possible to reduce the risk of disease progression.

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Section: Application Of Proteomics In the Emerging Pandemicmentioning

confidence: 82%

“…Based on this work, Acharya et al. 206 demonstrated that BRD2 is a potential target for development of therapeutics against SARS‐CoV‐2 in vitro. In another study, using proximity proteomics, Meyers et al.…”

Section: Application Of Proteomics In the Emerging Pandemicmentioning

confidence: 85%

Application of omics technology to combat the COVID‐19 pandemic

Yang

Yan²,

Zhong³

2021

MedComm

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“…The pan Akt inhibitor MK2206 resulted in a significant reduction in virus production as demonstrated by lower viral transcripts both in the cells and the supernatant [59] . Although inhibitors of different components of the PI3K/Akt/mTOR pathway did not show the same significant effect as MK2206 [59] , simultaneously targeting PI3K and mTOR, in addition to BRD2/BRD4, identified as therapeutic targets in COVID-19, using the inhibitor SF2523 (a small molecule inhibitor that targets the PI3K isoforms α and γ, mTOR, BRD4 and DNA-PK) was effective in blocking the replication of SARS-CoV-2 in bronchial epithelial cells [60] .…”

Section: Viral Loadmentioning

confidence: 96%

Targeting the PI3K/Akt/mTOR pathway: A therapeutic strategy in COVID-19 patients

Eid

Ward

2021

Immunology Letters

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Some COVID-19 patients suffer complications from anti-viral immune responses which can lead to both a dangerous cytokine storm and development of blood-borne factors that render severe thrombotic events more likely. The precise immune response profile is likely, therefore, to determine and predict patient outcomes and also represents a target for intervention. Anti-viral T cell exhaustion in the early stages is associated with disease progression. Dysregulation of T cell functions, which precedes cytokine storm development and neutrophil expansion in alveolar tissues heralds damaging pathology.T cell function, cytokine production and factors that attract neutrophils to the lung can be modified through targeting molecules that can modulate T cell responses. Manipulating T cell responses by targeting the PI3K/Akt/mTOR pathway could provide the means to control the immune response in COVID-19 patients. During the initial anti-viral response, T cell effector function can be enhanced by delaying anti-viral exhaustion through inhibiting PI3K and Akt. Additionally, immune dysregulation can be addressed by enhancing immune suppressor functions by targeting downstream mTOR, an important intracellular modulator of cellular metabolism. Targeting this signalling pathway also has potential to prevent formation of thrombi due to its role in platelet activation. Furthermore, this signalling pathway is essential for SARS-cov-2 virus replication in host cells and its inhibition could, therefore, reduce viral load. The ultimate goal is to identify targets that can quickly control the immune response in COVID-19 patients to improve patient outcome. Targeting different levels of the PI3K/Akt/mTOR signalling pathway could potentially achieve this during each stage of the disease.

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“…The antiviral potential of the compounds were screened as reported earlier (29). In brief, were calculated using four-parameter variable slope sigmoidal dose-response models using Graph Pad Prism 8.0 software.…”

Section: Assessment Of Antiviral Activity Of Selected Compoundsmentioning

confidence: 99%

Discovery and Evaluation of Entry Inhibitors for SARS-CoV-2 and Its Emerging Variants

Acharya

Pandey

Thurman

et al. 2021

J Virol

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The outbreak of SARS-CoV-2 is responsible for the COVID-19 pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design (CADD) approach, we identified and validated 5 potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both the compounds showed antiviral activity with IC 50 values in the micromolar range (MU-UNMC-1: IC 50 = 0.67 μM and MU-UNMC-2: IC 50 = 1.72 μM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC 50 = 9.27 μM & 3.00 μM) and Scotland variant B.1.222 (IC 50 = 2.64 μM & 1.39 μM) respectively. Following these assays, we conducted ‘induced-fit (flexible) docking’ to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir (RDV), the only approved drug for treating hospitalized COVID-19 patients. IMPORTANCE The ongoing coronavirus infectious disease 2019 (COVID-19) pandemic is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More than 207 million people have been infected globally, and 4.3 million have died due to this viral outbreak. While a few vaccines have been deployed, a SARS-CoV-2 specific antiviral for the treatment of COVID-19 is yet to be approved. As the interaction of SARS-CoV-2 spike protein with ACE2 is critical for cellular entry, using a combination of a computer-aided drug design (CADD) approach and cell-based in vitro assays, we report the identification of five potential SARS-CoV-2 entry inhibitors. Out of the five, two compounds (MU-UNMC-1 and MU-UNMC-2) have antiviral activity against ancestral SARS-CoV-2 and emerging variants from South Africa and Scotland. Furthermore, MU-UNMC-2 acts synergistically with remdesivir, suggesting that RDV and MU-UNMC-2 can be developed as a combination therapy to treat COVID-19, infected individuals.

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Blockade of SARS-CoV-2 infection in vitro by highly potent PI3K-α/mTOR/BRD4 inhibitor

Cited by 14 publications

References 62 publications

Application of omics technology to combat the COVID‐19 pandemic

Application of omics technology to combat the COVID‐19 pandemic

Targeting the PI3K/Akt/mTOR pathway: A therapeutic strategy in COVID-19 patients

Discovery and Evaluation of Entry Inhibitors for SARS-CoV-2 and Its Emerging Variants

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