Identification of potent small molecule inhibitors of SARS-CoV-2 entry

Jablonski, Sonia Mediouni; Mou, Huihui; Otsuka, Yuka; Jablonski, Joseph; Adcock, Robert S.; Batra, Lalit; Chung, Donghoon; Rood, Christopher; Vera, Ian Mitchelle S. de; Rahaim, Ronald J.; Ullah, Sultan; Yu, Xuerong; Nguyen, Tu-Trinh; Hull, Mitchell V.; Chen, Emily; Bannister, Thomas D.; Baillargeon, Pierre; Scampavia, Louis; Farzan, Michael; Valente, Susana T.; Spicer, Timothy

doi:10.1016/j.slasd.2021.10.012

Cited by 25 publications

(16 citation statements)

References 57 publications

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“…Calpeptin, the least efficacious compound tested in this study, has been identified in several SARS-CoV-2 drug screens 9,38,39 , even showing the highest antiviral activity in a screen based on x-ray crystallography and a SARS-CoV-2 screen on Vero E6 cells 9 . Despite this, no studies have reported its efficacy in animal models or clinical trials and its lack of efficacy in PREDICT96-ALI likely predicts its failure as a SARS-CoV-2 therapeutic.…”

Section: Discussionmentioning

confidence: 99%

Predicting clinical outcomes of SARS-CoV-2 drug treatments with a high throughput human airway on chip platform

Fisher¹,

Medie²,

Luu³

et al. 2022

Preprint

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Despite the relatively common observation of therapeutic efficacy in discovery screens with immortalized cell lines, the vast majority of drug candidates do not reach clinical development. Candidates that do move forward often fail to demonstrate efficacy when progressed from animal models to humans. This dilemma highlights the need for new drug screening technologies that can parse drug candidates early in development with regard to predicted relevance for clinical use. PREDICT96-ALI is a high-throughput organ-on-chip platform incorporating human primary airway epithelial cells in a dynamic tissue microenvironment. Here we demonstrate the utility of PREDICT96-ALI as an antiviral screening tool for SARS-CoV-2, combining the high-throughput functionality of a 96-well plate format in a high containment laboratory with the relevant biology of primary human tissue. PREDICT96-ALI resolved differential efficacy in five antiviral compounds over a range of drug doses. Complementary viral genome quantification and immunofluorescence microscopy readouts achieved high repeatability between devices and replicate plates. Importantly, results from testing the three antiviral drugs currently available to patients (nirmatrelvir, molnupiravir, and remdesivir) tracked with clinical outcomes, demonstrating the value of this technology as a prognostic drug discovery tool.

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Section: Discussionmentioning

confidence: 99%

Predicting clinical outcomes of SARS-CoV-2 drug treatments with a high throughput human airway on chip platform

Fisher¹,

Medie²,

Luu³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Another potential therapy for post-COVID-19 PF is the use of mesenchymal stem cell-derived EVs [ 74 ]. However, since much effort has been put into finding new, isoform-specific calpain inhibitors [ 75 ], with many of these also in clinical trials [ 13 , 73 ], drug repurposing of such selective inhibitors seems particularly advantageous and should be pursued to treat not just acute COVID-19 but also to manage the long-term effects of post-COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…In work in which libraries were screened for small molecule inhibitors for repurposing as entry inhibitor drugs, calpeptin was identified as having activity in in vitro infectivity assays. In Vero E6 cells with either low or high ACE2 expression, calpeptin (‘SR-914’) showed an EC 50 of 174 and 163 nM, respectively [ 13 ]. This study suggested several mechanisms of action, including blocking entry by preventing ACE2:S protein RBD interaction through high affinity binding of calpeptin to S protein RBD on the S1 subunit ( Figure 1 A(2)).…”

Section: Calpeptin As An Inhibitor Of Sars-cov-2 Uptakementioning

confidence: 99%

Therapeutic use of calpeptin in COVID-19 infection

2022

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This perspective considers the benefits of the potential future use of the cell permeant calpain inhibitor, calpeptin, as a drug to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recent work has reported calpeptin’s capacity to inhibit entry of the virus into cells. Elsewhere, several drugs, including calpeptin, were found to be able to inhibit extracellular vesicle (EV) biogenesis. Unsurprisingly, because of similarities between viral and EV release mechanisms, calpeptin has also been shown to inhibit viral egress. This approach, identifying calpeptin, through large-scale screening studies as a candidate drug to treat COVID-19, however, has not considered the longer term likely benefits of calpain inhibition, post-COVID-19. This perspective will reflect on the capacity of calpeptin for treating long COVID by inhibiting the overproduction of neutrophil extracellular traps potentially damaging lung cells and promoting clotting, together with limiting associated chronic inflammation, tissue damage and pulmonary fibrosis. It will also reflect on the tolerated and detrimental in vivo side-effects of calpain inhibition from various preclinical studies.

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“…Researchers have employed both in vitro binding and cell-based assays for screening and hit validation in order to identify inhibitors of Spike-receptor interaction. These include binding assays that utilise recombinant Spike and ACE2 proteins such as ELISA, SPR, differential scanning fluorimetry and cell-based assays that monitor entry of pseudo-typed luciferase reporter viruses bearing Spike protein ( Mediouni et al, 2022 ; Chen et al, 2020 ), or NanoBit-RBD/ACE2 PPI assays ( Yu et al, 2021 ). As well, in silico modelling and screening of potential binders in the RBD-Spike interaction site, followed by the use of machine learning and deep learning algorithms, have been extensively explored to identify novel binders and to facilitate rational design.…”

Section: Sars-cov-2 Entry Inhibitors In Clinical and Preclinical Testingmentioning

confidence: 99%

“…Besides interfering with virus-receptor interactions, repurposed drugs that block spike-mediated cell fusion ( Mediouni et al, 2022 ; Chen et al, 2020 ; Riva et al, 2020 ) or enzymatic activities of ACE2 (MLN-4760), TMPRSS2 (Camostat mesylate and Nafamostat), cathepsins (Eicoplanin, calpain inhibitor II, XII), furin (reviewed in Nepali et al, 2022 ) have been described. Indeed, a few repurposed drugs have entered the clinic for treatment of COVID-19 and they include Niclosamide (oral or inhaled formulation; phase III) which acts as a protonophore to interfere with viral entry and egress ( Singh et al, 2022 ), Nafamostat ( Zhuravel, 2021 ; phase II/III), Camostat (phase I/II), Amiodarone and Verapamil (inhibit endosomal processing ( Stadler et al, 2008 ; phase II/III), Umifenovir (Arbidol; targets S-protein and prevents viral fusion; Nojomi et al, 2020 ; phase III/IV).…”

Section: Sars-cov-2 Entry Inhibitors In Clinical and Preclinical Testingmentioning

confidence: 99%

Targeting SARS-CoV-2 and host cell receptor interactions

Lim

2023

Antiviral Research

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Identification of potent small molecule inhibitors of SARS-CoV-2 entry

Cited by 25 publications

References 57 publications

Predicting clinical outcomes of SARS-CoV-2 drug treatments with a high throughput human airway on chip platform

Predicting clinical outcomes of SARS-CoV-2 drug treatments with a high throughput human airway on chip platform

Therapeutic use of calpeptin in COVID-19 infection

Targeting SARS-CoV-2 and host cell receptor interactions

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