Pyronaridine Protects against SARS-CoV-2 Infection in Mouse

Puhl, Ana C.; Gomes, Giovanni Freitas; Damasceno, Samara; Godoy, Andre S.; Noske, G.D.; Nakamura, A.M.; Gawriljuk, V.O.; Fernandes, R.S.; Monakhova, Natalia; Riabova, Olga; Lane, Thomas R.; Makarov, Vadim; Veras, Flávio P.; Batah, Sabrina Setembre; Fabro, Alexandre Todorovic; Oliva, Glaucius; Cunha, Fernando Q.; Alves‐Filho, José C.; Cunha, Thiago Mattar; Ekins, Sean

doi:10.1021/acsinfecdis.2c00091

Cited by 22 publications

(39 citation statements)

References 81 publications

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“…Lungs were used for ELISA assay, viral load analysis, and histological assessment, as described previously. 64 …”

Section: Methodsmentioning

confidence: 99%

“…ELISA assay was performed with lung homogenate as described previously. 64 The following cytokines and chemokines were measured: IL-6, IL-10, IL-1β, TNF-α, IFN-1β, CXCL1, CXCL2, CXCL10, CCL2, CCL3, and CCL4.…”

Section: Methodsmentioning

confidence: 99%

“…Lung histopathology was performed as described previously. 64 Morphometric analysis was conducted in accordance the American Thoracic Society and European Thoracic Society (ATS/ERS) protocol. 72 …”

Section: Methodsmentioning

confidence: 99%

“…SARS-CoV-2 was isolated from a COVID-19 positive-tested patient . We used K18-hACE2 humanized mice (B6.Cg-Tg(K18-ACE2)2Prlmn/J) ,, from Jackson Laboratory, which has been used as model for SARS-CoV-2-induced disease. − Mice were breed in the Centro de Criação de Animais Especiais (Ribeirão Preto Medical School/University of São Paulo).…”

Section: Methodsmentioning

confidence: 99%

“…A total of 800 ng of RNA from the lung was used to synthesize cDNA. cDNA synthesis and the absolute copy quantification were performed as described previously …”

Section: Methodsmentioning

confidence: 99%

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Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

et al. 2022

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The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib is a kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), as well as the RET-tyrosine kinase. In the current study, it was tested in different cell lines and showed promising results on inhibition versus the toxic effect on A549-hACE2 cells (IC 50 0.79 μM) while also showing a reduction of >3 log TCID 50 /mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, and TNF-α and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib also decreased CCL2, CCL3, and CCL4 compared to the infected animals. Vandetanib additionally rescued the decreased IFN-1β caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved anticancer drug vandetanib is worthy of further assessment as a potential therapeutic candidate to block the COVID-19 cytokine storm.

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“…Lungs were used for ELISA assay, viral load analysis, and histological assessment, as described previously. 64 …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…A total of 800 ng of RNA from the lung was used to synthesize cDNA. cDNA synthesis and the absolute copy quantification were performed as described previously …”

Section: Methodsmentioning

confidence: 99%

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Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

et al. 2022

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Exploring the druggability of the UEV domain of human TSG101 in search for broad‐spectrum antivirals

Montero,

Parra‐López,

Rodríguez‐Martínez

et al. 2024

Protein Science

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The ubiquitin E2 variant domain of TSG101 (TSG101‐UEV) plays a pivotal role in protein sorting and virus budding by recognizing PTAP motifs within ubiquitinated proteins. Disruption of TSG101‐UEV/PTAP interactions has emerged as a promising strategy for the development of host‐oriented broad‐spectrum antivirals with low susceptibility to resistance. TSG101 is a challenging target characterized by an extended and flat binding interface, low affinity for PTAP ligands, and complex binding energetics. Here, we assess the druggability of the TSG101‐UEV/PTAP binding interface by searching for drug‐like inhibitors and evaluating their ability to block PTAP recognition, impair budding, and inhibit viral proliferation. A discovery workflow was established by combining in vitro miniaturized HTS assays and a set of cell‐based activity assays including high‐content bimolecular complementation, virus‐like particle release measurement, and antiviral testing in live virus infection. This approach has allowed us to identify a set of chemically diverse molecules that block TSG101‐UEV/PTAP binding with IC50s in the low μM range and are able to disrupt the interaction between full‐length TSG101 and viral proteins in human cells and inhibit viral replication. State‐of‐the‐art molecular docking studies reveal that the active compounds exploit binding hotspots at the PTAP binding site, unlocking the full binding potential of the TSG101‐UEV binding pockets. These inhibitors represent promising hits for the development of novel broad‐spectrum antivirals through targeted optimization and are also valuable tools for investigating the involvement of ESCRT in the proliferation of different virus families and study the secondary effects induced by the disruption of ESCRT/virus interactions.

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In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing

et al. 2023

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Background In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron. Methods As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site. Results The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of − 75.7304 ± 0.98324 and − 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study. Graphical Abstract

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Pyronaridine Protects against SARS-CoV-2 Infection in Mouse

Cited by 22 publications

References 81 publications

Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

Exploring the druggability of the UEV domain of human TSG101 in search for broad‐spectrum antivirals

In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing

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