100 Years of Suramin

Wiedemar, Natalie; Hauser, Dennis A.; Mäser, Pascal

doi:10.1128/aac.01168-19

Cited by 128 publications

(134 citation statements)

References 179 publications

(118 reference statements)

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“…Possible mechanisms include inhibiting important enzymes, such as cullin-RING E3 ubiquitin ligases 62 , protein-tyrosine phosphatases 40 , and blocking various growth factors binding to their receptors 41 . In fact, suramin has “so many” targets that its cellular and physiological activities are expected to stem from not just one single target but multiple targets 63 . Here we reveal another potential target, HMGA2 and/or HMGA proteins for this intriguing small molecule.…”

Section: Discussionmentioning

confidence: 99%

Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays

Bryan

Battista

et al. 2020

Sci Rep

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The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNA-binding protein that plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen ultra-high-throughput screening assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we identified several compounds that strongly inhibit HMGA2-DNA interactions including suramin, a century-old, negatively charged antiparasitic drug. Our results show that the inhibition is likely through suramin binding to the “AT-hook” DNA-binding motifs and therefore preventing HMGA2 from binding to the minor groove of AT-rich DNA sequences. Since HMGA1 proteins also carry multiple “AT-hook” DNA-binding motifs, suramin is expected to inhibit HMGA1-DNA interactions as well. Biochemical and biophysical studies show that charge-charge interactions and hydrogen bonding between the suramin sulfonated groups and Arg/Lys residues play critical roles in the binding of suramin to the “AT-hook” DNA-binding motifs. Furthermore, our results suggest that HMGA2 may be one of suramin’s cellular targets.

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Section: Discussionmentioning

confidence: 99%

Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays

Bryan

Battista

et al. 2020

Sci Rep

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“…Suramin derivatives have been explored for diverse applications including anti-cancers and antiparasites (Wiedemar et al, 2020). To determine the structure-activity-relationship (SAR), we screened a set of 8 different suramin derivatives using in vitro RdRp primer extension assays ( Figure 6A and Figure S1F).…”

Section: Inhibition Sars-cov-2 Rdrp By Suramin Derivativesmentioning

confidence: 99%

“…Suramin has also been shown to be effective in inhibiting the replication of a wide spectrum of viruses, including enteroviruses (Ren et al, 2014), Zika virus (Albulescu et al, 2017), Chikungunya (Albulescu et al, 2015) and Ebola viruses (Henß et al, 2016). The viral inhibition mechanism of suramin appears to be very diverse, including inhibition of viral attachment, entry, and release from host cells in part through interactions with viral capsid proteins (Wiedemar et al, 2020). Recently, suramin has been shown to inhibit SARS-CoV-2 infection in cell culture, which was proposed to act through preventing entry of the virus (Salgado-Benvindo et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19

Yin

Luan

et al. 2020

Preprint

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SUMMARYThe COVID-19 pandemic by non-stop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report the discovery of suramin, a 100-year-old drug, as a potent inhibitor of the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) through blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for COVID-19. The 2.6 Å cryo-EM structure of the viral RdRp bound to suramin reveals two binding sites of suramin, with one site directly blocking the binding of the RNA template strand and the other site clash with the RNA primer strand near the RdRp catalytic active site, therefore inhibiting the viral RNA replication. Furthermore, suramin potently inhibits SARS-CoV-2 duplication in Vero E6 cells. These results provide a structural mechanism for the first non-nucleotide inhibitor of the SARS-CoV-2 RdRp and a rationale for repurposing suramin for treating COVID-19.One Sentence SummaryDiscovery and mechanism of suramin as potent SARS-CoV-2 RNA polymerase inhibitor and its repurposing for treating COVID-19.

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“…Suramin derivatives have been explored for diverse applications including anti-cancers and antiparasites 10 . To determine the structure-activity-relationship (SAR), we screened a set of 8 different suramin derivatives using in vitro RdRp primer extension assays ( Fig.…”

Section: Inhibition Sars-cov-2 Rdrp By Suramin Derivativesmentioning

confidence: 99%

“…Suramin has also been shown to be effective in inhibiting the replication of a wide spectrum of viruses, including enteroviruses 6 , Zika virus 7 , Chikungunya 8 and Ebola viruses 9 . The viral inhibition mechanism of suramin appears to be very diverse, including inhibition of viral attachment, entry, and release from host cells in part through interactions with viral capsid proteins 10 . Recently, suramin has been shown to inhibit SARS-CoV-2 infection in cell culture, which was proposed to act through preventing entry of the virus 11 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19

Yin

Luan

et al. 2020

Preprint

View full text Add to dashboard Cite

The COVID-19 pandemic by non-stop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report the discovery of suramin, a 100-year-old drug, as a potent inhibitor of the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) through blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for COVID-19. The 2.6 Å cryo-EM structure of the viral RdRp bound to suramin reveals two binding sites of suramin, with one site directly blocking the binding of the RNA template strand and the other site clash with the RNA primer strand near the RdRp catalytic active site. Furthermore, suramin potently inhibits SARS-CoV-2 duplication in Vero E6 cells. These results provide a structural mechanism for the first non-nucleotide inhibitor of the SARS-CoV-2 RdRp and a rationale for repurposing suramin for treating COVID-19.

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100 Years of Suramin

Cited by 128 publications

References 179 publications

Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays

Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays

Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19

Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19

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