Suramin Inhibits SARS-CoV-2 Infection in Cell Culture by Interfering with Early Steps of the Replication Cycle

Salgado-Benvindo, Clarisse; Thaler, Melissa; Taş, Ali; Ogando, Natacha S.; Bredenbeek, Peter J.; Ninaber, Dennis K.; Wang, Ying; Hiemstra, Pieter S.; Snijder, Eric J.; Hemert, Martijn J. van

doi:10.1128/aac.00900-20

Cited by 94 publications

(84 citation statements)

References 39 publications

(52 reference statements)

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“…Our GO clustering analyses detected clustering of great significance for annotations such as establishment of RNA localization, cell projection, lyase activity, cell cycle and more. These fall in line with the current literature which describes such disturbances upon SARS-CoV-2 infection 40–42 and could also represent putative therapeutic targets. This collection of GO terms also helps shed light on the host mechanisms hijacked by SARS-CoV-2.…”

Section: Discussionsupporting

confidence: 90%

Computational identification of human biological processes and protein sequence motifs putatively targeted by SARS-CoV-2 proteins using protein-protein interaction networks

Nadeau

Fard

Scheer

et al. 2020

Preprint

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While the COVID-19 pandemic is causing important loss of life, knowledge of the effects of the causative SARS-CoV-2 virus on human cells is currently limited. Investigating protein-protein interactions (PPIs) between viral and host proteins can provide a better understanding of the mechanisms exploited by the virus and enable the identification of potential drug targets. We therefore performed an in-depth computational analysis of the interactome of SARS-CoV-2 and human proteins in infected HEK293 cells published by Gordon et al. to reveal processes that are potentially affected by the virus and putative protein binding sites. Specifically, we performed a set of network-based functional and sequence motif enrichment analyses on SARS-CoV-2-interacting human proteins and on a PPI network generated by supplementing viral-host PPIs with known interactions. Using a novel implementation of our GoNet algorithm, we identified 329 Gene Ontology terms for which the SARS-CoV-2-interacting human proteins are significantly clustered in the network. Furthermore, we present a novel protein sequence motif discovery approach, LESMoN-Pro, that identified 9 amino acid motifs for which the associated proteins are clustered in the network. Together, these results provide insights into the processes and sequence motifs that are putatively implicated in SARS-CoV-2 infection and could lead to potential therapeutic targets.

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Section: Discussionsupporting

confidence: 90%

Computational identification of human biological processes and protein sequence motifs putatively targeted by SARS-CoV-2 proteins using protein-protein interaction networks

Nadeau

Fard

Scheer

et al. 2020

Preprint

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“…In fact, this assay setup is very similar to one recently shown to work as a specific and sensitive SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of this same PPI (CoV-S-ACE2) (Tan et al, 2020). With this setup in our hands, we performed a preliminary screening of representative organic dyes from our in-house library plus a few compounds that are or have been considered of possible interest in inhibiting SAR-CoV-2 by different mechanisms of action, e.g., chloroquine, clemastine, and suramin (Colson et al, 2020;da Silva et al, 2020;Gordon et al, 2020;McKee et al, 2020;Xiu et al, 2020). Screening at 5 µM indicated that most have no activity and, hence, are unlikely to interfere with the S-protein -ACE2 binding needed for viral attachment.…”

Section: Resultsmentioning

confidence: 99%

Methylene Blue Inhibits In Vitro the SARS-CoV-2 Spike – ACE2 Protein-Protein Interaction – A Mechanism That Can Contribute to Its Antiviral Activity Against COVID-19

Bojadzic

Garnica

Buchwald

2020

Preprint

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Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC50 = 3 μM) in our protein-based ELISA-type setup, while chloroquine, siramesine, and suramin showed no inhibitory activity in this assay. Erythrosine B, which we have shown before to be a promiscuous SMI of PPIs, also inhibited this interaction with an activity similar, possibly slightly higher, than those found for it for other PPIs. This PPI inhibitory activity of methylene blue could contribute to its antiviral activity against SARS-CoV-2 even in the absence of light by blocking its attachment to ACE2-expressing cells and making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.

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“…Multiple studies have also revealed that suramin interferes with viral RNA synthesis by targeting viral RNA-dependent RNA polymerase (Albulescu et al, 2015;Mastrangelo et al, 2012). A recent study by de Silva et al demonstrated suramin inhibited SARS-CoV-2 replication in Vero E6 cells and reduced viral RNA in Calu-3 cells (da Silva et al, 2020). The authors proposed prevention of SARS-CoV-2 viral entry into cells as a mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-throughput Screening

Zhu

Chen

et al. 2020

Preprint

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Background and PurposeThe COVID-19 caused by SARS-CoV-2 has emphasized the urgent need for therapeutic development. Drug repurposing screening is the most practical and rapid approach for discovery of such therapeutics. The 3CLpro, or main protease (Mpro) of SARS-CoV-2 is a valid drug target as it is a viral enzyme with an essential role in viral replication, and cleavage specificity that is distinct from host proteases.Experimental ApproachWe employed and miniaturized a fluorogenic 3CLpro enzyme assay in which 3CLpro cleaves a quenched peptide substrate and releases a fluorescent fragment, resulting an increase in fluorescence signal. By using this SARS-CoV-2 3CLpro assay, we conducted a qHTS of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds, at 4 compound concentrations. The confirmed 3CLpro inhibitors were also tested in a SARS-CoV-2 cytopathic effect assay to determine their effects on rescuing of cell death caused by the virus infection.Key ResultsTwenty-seven small molecule inhibitors of SARS-CoV-2 3CLpro have been identified with IC50s ranging from 0.26 to 27.1 μM with a greater than 80% maximal inhibition. Walrycin B (IC50 = 0.26 μM), Hydroxocobalamin (IC50 = 3.29 μM), Suramin sodium (IC50 = 6.50 μM), Z-DEVD-FMK (IC50 = 6.81 μM), and LLL-12 (IC50 = 9.84 μM) are the most potent 3CLpro inhibitors with IC50s under 10 μM. The activities of anti-SARS-CoV-2 viral infection were confirmed in 11 of 27 compounds.Conclusion and ImplicationsSome of the newly identified inhibitors of SARS-CoV-2 3CLpro may be used in combination therapy with other drugs for synergistic effect to treat COVID-19 patients. The other inhibitors found in this study can provide starting points for medicinal chemistry optimizations.Bullet point summaryWhat is already knownSARS-CoV-2 3CLpro is a valid target for drug development.What this study addsIdentification of 27 inhibitors of SARS-CoV-2 3CLpro by a qHTS of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds.Clinical significanceSome of the newly identified 3CLpro inhibitors can be evaluated in drug combination therapy for synergistic effect to treat COVID-19 patients, while the others can serve as starting points for medicinal chemistry optimization to improve potency and drug like properties for drug development.

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Suramin Inhibits SARS-CoV-2 Infection in Cell Culture by Interfering with Early Steps of the Replication Cycle

Cited by 94 publications

References 39 publications

Computational identification of human biological processes and protein sequence motifs putatively targeted by SARS-CoV-2 proteins using protein-protein interaction networks

Computational identification of human biological processes and protein sequence motifs putatively targeted by SARS-CoV-2 proteins using protein-protein interaction networks

Methylene Blue Inhibits In Vitro the SARS-CoV-2 Spike – ACE2 Protein-Protein Interaction – A Mechanism That Can Contribute to Its Antiviral Activity Against COVID-19

Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-throughput Screening

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