SIRT1 (IC50 = 297 nM); SIRT2 (IC50 = 1.15 μM); SIRT5 (IC50 = 22 μM)
In a dose-dependent and time-regulated manner, suramin sodium salt (also known as suramin hexasodium salt; 50-600 μg/mL; lasting 24-96 hours) suppresses cell proliferation and lowers lymphocyte viability [7]. mL; for 48 hours) causes HeLa cells to undergo apoptosis and express less mRNA [7]. One hour of 1 mg/mL suramin sodium salt suppresses phosphorylated ERK1/2 substantially [8]. HeLa and PM have IC50 values of 476 μg/mL and 319 μg/mL, respectively [7]. In Vero E6 cells, suramin sodium salt increases viral replication [5].

In a dose-dependent and time-regulated manner, suramin sodium salt (also known as suramin hexasodium salt; 50-600 μg/mL; lasting 24-96 hours) suppresses cell proliferation and lowers lymphocyte viability [7]. mL; for 48 hours) causes HeLa cells to undergo apoptosis and express less mRNA [7]. One hour of 1 mg/mL suramin sodium salt suppresses phosphorylated ERK1/2 substantially [8]. HeLa and PM have IC50 values of 476 μg/mL and 319 μg/mL, respectively [7]. In Vero E6 cells, suramin sodium salt increases viral replication [5].

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Suramin is a reversible, competitive, and tight-binding inhibitor of protein-tyrosine phosphatases (PTPases). It inhibits PTP1B with a Ki of 4 µM and the Yersinia PTPase with a Ki of 1.3 µM, as determined by steady-state kinetic inhibition assays using p-nitrophenyl phosphate (pNPP) as substrate.
Suramin inhibits the dual specificity phosphatase VHR with a Ki of 48 µM, which is at least 10-fold higher than for PTP1B and the Yersinia PTPase.
Suramin also inhibits potato acid phosphatase (noncompetitive, Ki = 9.3 µM, Kii = 11.2 µM) and bovine intestinal alkaline phosphatase (competitive, Ki = 1.4 mM), but is 2-3 orders of magnitude less effective against protein Ser/Thr phosphatase 1α (noncompetitive, Ki = 250 µM).
Binding studies using fluorescence spectroscopy show that suramin binds to the active site of PTPases with a stoichiometry of 1:1. The binding is rapid (reaches equilibrium within minutes) and reversible.
Upon binding to PTPases, the fluorescence of suramin (excitation at 315 nm) is enhanced approximately 10-fold (emission λmax = 405 nm). This property was used for fluorescence titration to determine dissociation constants (Kd). The Kd for PTP1B was 1.4 µM and for the Yersinia PTPase was 3.0 µM, consistent with Ki values.
Active site mutants of PTPases were used to characterize binding. The general acid-deficient mutants (PTP1B/D181A and Yersinia PTP/D356A) displayed ~5-fold higher affinity for suramin compared to wild-type enzymes. The active site arginine mutant (Yersinia PTP/R409A) exhibited a 20-fold reduced affinity, while active site cysteine to serine mutants (PTP1B/C215S, Yersinia PTP/C403S) bound suramin with similar affinity as wild-type.
Vanadate, a known competitive inhibitor binding at the PTPase active site, displaced suramin from PTP1B and the Yersinia PTPase in fluorescence competition experiments, confirming shared binding sites.
The observed increase in tyrosine phosphorylation of several cellular proteins in cancer cell lines upon suramin treatment is consistent with its inhibitory activity against cellular PTPases.

Suramin hexasodium salt (Suramin hexasodium salt; form 10 mg/kg; intravenously; twice weekly for 3 weeks) reverses established pulmonary hypertension (PH), consequently improving pulmonary artery pressure values and vascular structure Normal [8].

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Suramin (Sur) acts as an ecto-NTPDase inhibitor in Trypanosoma cruzi and a P2-purinoceptor antagonist in mammalian cells. Although the potent antitrypanosomal effect of Sur has been shown in vitro, limited evidence in vivo suggests that this drug can be dangerous to T. cruzi-infected hosts. Therefore, we investigated the dose-dependent effect of Sur-based chemotherapy in a murine model of Chagas disease. Seventy uninfected and T. cruzi-infected male C57BL/6 mice were randomized into five groups: SAL = uninfected; INF = infected; SR5, SR10, and SR20 = infected treated with 5, 10, or 20 mg/kg Sur. In addition to its effect on blood and heart parasitism, the impact of Sur-based chemotherapy on leucocytes myocardial infiltration, cytokine levels, antioxidant defenses, reactive tissue damage, and mortality was analyzed. Our results indicated that animals treated with 10 and 20 mg/kg Sur were disproportionally susceptible to T. cruzi, exhibiting increased parasitemia and cardiac parasitism (amastigote nests and parasite load (T. cruzi DNA)), intense protein, lipid and DNA oxidation, marked myocarditis, and mortality. Animals treated with Sur also exhibited reduced levels of nonprotein antioxidants. However, the upregulation of catalase, superoxide dismutase, and glutathione-S-transferase was insufficient to counteract reactive tissue damage and pathological myocardial remodeling. It is still poorly understood whether Sur exerts a negative impact on the purinergic signaling of T. cruzi-infected host cells. However, our findings clearly demonstrated that through enhanced parasitism, inflammation, and reactive tissue damage, Sur-based chemotherapy contributes to aggravating myocarditis and increasing mortality rates in T. cruzi-infected mice, contradicting the supposed relevance attributed to this drug for the treatment of Chagas disease.[7]

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Researchers evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen. Conclusions: RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension [8].

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In a murine model of Chagas disease (C57BL/6 mice infected with _T. cruzi_, Y strain), treatment with Suramin at 10 and 20 mg/kg for 15 consecutive days via intraperitoneal injection significantly worsened the disease outcomes compared to untreated infected mice. [7]
Suramin treatment (10 and 20 mg/kg) increased parasitemia (mean and peak) and mortality rates in a dose-dependent manner. The 20 mg/kg group showed the highest parasitemia and 64.3% mortality. [7]
Suramin treatment (especially 10 and 20 mg/kg) enhanced cardiac parasitism, evidenced by increased numbers of _T. cruzi_ amastigote nests and higher parasite DNA load (quantified by qPCR) in heart tissue. [7]
Suramin treatment aggravated myocarditis, leading to intense diffuse inflammatory infiltrate (increased mononuclear and polymorphonuclear cells), reduced contractile parenchyma, and expansion of connective stroma in the heart. [7]
Suramin treatment (10 and 20 mg/kg) elevated cardiac levels of pro-inflammatory cytokines TNF-α and IFN-γ, as well as nitric oxide (estimated as nitrite/nitrate). [7]
Suramin treatment exacerbated oxidative stress in the heart, indicated by increased levels of lipid oxidation marker malondialdehyde (MDA), protein carbonyls (PCn, marker of protein oxidation), and DNA oxidation marker 8-hydroxy-2′-deoxyguanosine (8-OHdG). [7]
Suramin treatment (10 and 20 mg/kg) increased the activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione-S-transferase) but depleted non-protein antioxidant capacity in the heart. This compensatory upregulation was insufficient to counteract the severe reactive tissue damage. [7]
The study concluded that Suramin-based chemotherapy, by enhancing parasitism, inflammation, and reactive tissue damage, aggravates myocarditis and increases mortality in _T. cruzi_-infected mice. [7]

Receptor tyrosine kinase phosphorylation assay [8]
\nPA-SMCs cultured in DMEM supplemented with 10% FCS were synchronized for 48 hours. After preincubation with suramin (1000 µg/mL) for 1 hour, the cells were stimulated with a combination of PDGF, EGF and FGF2 for 15 minutes at 37°C. The relative levels of tyrosine phosphorylation of the RTKs in the PA-SMCs were determined using the Proteome Profiler™ Human Phospho-RTK Array kit in accordance with the manufacturer's protocol. Briefly, cells were lysed in ice-cold lysis buffer and 150 µg of total protein was used for the assay. Densitometric quantification of the immunoblot dots was performed using semi-automated image analysis.\n

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\nThe effect of suramin , a well known antitrypanosomal drug and a novel experimental agent for the treatment of several cancers, on protein-tyrosine phosphatases (PTPases) has been examined. Suramin is a reversible and competitive PTPase inhibitor with Kis values in the low microM range, whereas the Kis for the dual specificity phosphatase VHR is at least 10-fold higher. Although suramin can also inhibit the activity of the potato acid phosphatase at a slightly higher concentration, it is 2-3 orders of magnitude less effective against the protein Ser/Thr phosphatase 1alpha and the bovine intestinal alkaline phosphatase. Suramin binds to the active site of PTPases with a binding stoichiometry of 1:1. Furthermore, when suramin is bound to the active site of PTPases, its fluorescence is enhanced approximately by 10-fold. This property has allowed the determination of the binding affinity of suramin for PTPases and several catalytically impaired mutant PTPases by fluorescence titration techniques. Thus, the active site Cys to Ser mutants bind suramin with similar affinity as the wild type, while the active site Arg to Ala mutant exhibits a 20-fold reduced affinity toward suramin. Interestingly, the general acid deficient Asp to Ala mutant PTPases display an enhanced affinity toward suramin, which is in accord with their use as improved \"substrate-trapping\" agents. That suramin is a high affinity PTPase inhibitor is consistent with the observation that suramin treatment of cancer cell lines leads to an increase in tyrosine phosphorylation of several cellular proteins. Given the pleiotropic effects of suramin on many enzyme systems and growth factor-receptor interactions, the exact in vivo actions of suramin require further detailed structure-activity investigation of suramin and its structural analogs.[1]\n

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\nSirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified suramin as a compound that binds to human SIRT5 and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to suramin. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that suramin binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors.[3]\n

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\nThe COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin , a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by 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 treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.[5] \n\n

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\nSuramin is a symmetric polyanionic naphthylurea originally used for the treatment of trypanosomiasis and onchocerciasis. Suramin and diverse analogues exhibit a broad range of biological actions in vitro and in vivo, including, among others, antiproliferative and antiviral activity. Suramin derivatives usually target purinergic binding sites. Class III histone deacetylases (sirtuins) are amidohydrolases that require nicotinamide adenine dinucleotide (NAD(+)) as a cofactor for their catalytic mechanism(.) Deacetylation of the target proteins leads to a change in conformation and alters the activity of the proteins in question. Suramin was reported to inhibit human sirtuin 1 (SIRT1). We tested a diverse set of suramin analogues to elucidate the inhibition of the NAD(+)-dependent histone deacetylases SIRT1 and SIRT2 and discovered selective inhibitors of human sirtuins with potency in the two-digit nanomolar range. In addition, the structural requirements for the binding of suramin derivatives to sirtuins were investigated by molecular docking. The recently published X-ray crystal structure of human SIRT5 in complex with suramin and the human SIRT2 structure were used to analyze the interaction mode of the novel suramin derivatives[2].

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PTPase Activity Inhibition Assay: The activity of recombinant human PTP1B (catalytic domain), Yersinia PTPase (catalytic domain), and dual specificity phosphatase VHR was assayed at 25°C in buffer containing 50 mM 3,3-dimethylglutarate, pH 7.0, with ionic strength adjusted to 0.15 M using NaCl. The substrate was p-nitrophenyl phosphate (pNPP). The reaction was initiated by enzyme addition and quenched after 2-3 min with 1 N NaOH. The amount of p-nitrophenol produced was determined by absorbance at 405 nm. To determine inhibition constants (Ki), initial reaction rates were measured at various fixed concentrations of suramin and various pNPP concentrations. Data were fitted to competitive inhibition equations.
Other Phosphatase Inhibition Assays: The effects of suramin on potato acid phosphatase (assay buffer: 100 mM sodium acetate, pH 5.0), bovine intestinal alkaline phosphatase (assay buffer: 100 mM Tris, 1.0 mM MgCl2, pH 8.0), and protein Ser/Thr phosphatase 1α (assay buffer: 50 mM 3,3-dimethylglutarate, 2 mM DTT, 0.2 mM MnCl2, pH 7.0) were evaluated similarly using pNPP as substrate.
Fluorescence Titration for Binding Affinity: A spectrofluorimeter was used. A solution containing a fixed concentration of suramin (e.g., 4 µM) in assay buffer was titrated with increasing concentrations of PTPase. Emission spectra (370–480 nm) were recorded with excitation at 315 nm. The fluorescence intensity at 405 nm was monitored. The increase in fluorescence upon binding was used to calculate the dissociation constant (Kd) by fitting the titration data to a 1:1 binding model equation, correcting for the small intrinsic fluorescence of the protein and free suramin.
Binding Stoichiometry (Job Plot): The total concentration of suramin and PTPase was kept constant (e.g., 20 µM) while their molar ratio was varied. The fluorescence intensity of the mixture was measured. The maximum fluorescence occurred at a suramin-to-protein ratio of 1:1, indicating a 1:1 binding stoichiometry.
Reversibility and Competition Experiments: To assess reversibility, a pre-formed complex of suramin and PTPase (e.g., 40 µM each) was diluted 100-fold, and the fluorescence and enzyme activity of the diluted sample were measured and compared to a fresh mixture. To confirm active site binding, vanadate (1 mM) was added to a pre-formed suramin-PTPase complex, and the decrease in suramin fluorescence was monitored, indicating displacement.

Cell proliferation experiment[6]
Cell Types: HO-8910 PM ovarian cancer cells and HeLa cervical cancer cells
Tested Concentrations: 50, 100, 200, 300, 400, 500 and 600 μg/mL
Incubation Duration: 24, 48, 72 and 96 hrs (hours)
Experimental Results: Cell proliferation was inhibited in a dose- and time-dependent manner.

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Apoptosis analysis [6]
Cell Types: HeLa Cell
Tested Concentrations: 300 μg/mL
Incubation Duration: 48 hrs (hours)
Experimental Results: Induction of apoptosis.

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Western Blot Analysis[7]
Cell Types: PA-SMCs Cell
Tested Concentrations: 1 mg/mL
Incubation Duration: 1 hour
Experimental Results: Dramatically inhibited phosphorylated ERK1/2. \n

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\nFlow cytometry assessment of apoptosis [8]
\nApoptosis was detected using the Annexin V-fluorescein isothiocyanate (FITC) Apoptosis Detection Kit I. PA-SMCs were treated with suramin (1000 µg/mL). After 24 h, the culture medium containing the detached cells was collected. The plates were rinsed with phosphate buffered saline (PBS), and the cells were detached using 0.05% trypsin/EDTA and combined with their medium and floating cells. The cells were washed twice in cold PBS and resuspended at a density of 106 cells/mL in the binding buffer provided. Each sample was incubated with 5 µL of each of the provided Annexin V-FITC and propidium iodide (PI) solutions for 15 min in the dark. The sample volumes were then increased to 500 µL, and the samples were run using CyAn.\n

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\nIsolation, culture, and proliferation tests of human PA-SMCs [8]
\nPA-SMCs were isolated and cultured as previously described. The cells were subjected to 48 hours of growth arrest in serum-free medium and were then treated with suramin 1 h before incubation with 10% FCS. We also tested the effect of suramin on the growth response to exogenous PDGF (10 ng/mL), EGF (10 ng/mL), or FGF2 (10 ng/mL). For each condition, the cells were incubated for 24 hours and PA-SMC proliferation was then measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and by direct cell counting.\n

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\nOrgan culture of human pulmonary arteries [8]
\nEx vivo organ culture of human pulmonary arteries (hPA) was performed as previously described. Briefly, the arteries were obtained from patients, and segments 1 cm in length were prepared for ex vivo organ culture. The tissues were then incubated in culture medium that was either unsupplemented or supplemented with 10% FCS, suramin (1000 µg/mL), or masitinib (10-5 M) for ten days. The segments were fixed in 4% buffered paraformaldehyde and embedded in paraffin before being serially sectioned at 5 μm thickness and prepared for immunostaining and double immunofluorescence staining.\n

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\nSuramin, a polysulfonated naphthylurea widely used in the treatment of trypanosomiasis and onchocerciasis, is currently being investigated as an antitumor agent for the treatment of advanced cancer. Suramin exerts a wide variety of biological effects. We have shown that suramin inhibits cell proliferation and DNA synthesis in cultured HeLa cells. The replication in vitro of SV40 DNA is completely abolished by 40 microM suramin. The inhibition of DNA replication is due to inhibition of DNA polymerases alpha and delta, the replicative enzymes in eukaryotic cells. DNA polymerase alpha is sensitive to lower concentrations of suramin [concentration to achieve 50% inhibition (IC50) of 8 microM] than is DNA polymerase delta (IC50 36 microM), whereas DNA polymerase beta is relatively insensitive to the drug (IC50 of 90 microM). Suramin inhibits other replicative DNA polymerases such as Escherichia coli polymerase I (Klenow fragment) and Thermus aquaticus polymerase. Suramin is noncompetitive with both substrate deoxyribonucleotides and template-primers with respect to DNA polymerase inhibition. Much lower concentrations (8-30 microM) of the drug are required for 50% inhibition of DNA polymerases than for 50% inhibition of other enzymes such as protein kinase C and reverse transcriptase. These results show an important biological effect of this drug and indicate the need for more studies before its clinical use as an antitumor agent [6].\n

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Vero E6 cell-based antiviral assay: Vero E6 cells are seeded (5 × 10⁴ cells per well) and pre-incubated with different concentrations of suramin or its derivatives for 1 hour. Cells are then infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.01. After 2 hours, the virus-drug mixture is replaced with fresh compound-containing medium. At 24 hours post-infection, viral RNA copy number in the supernatant is quantified by real-time PCR. [5]
Cytotoxicity assay (CCK8): The cytotoxicity of suramin and its derivatives on Vero E6 cells is determined using a CCK8 assay. [5]

Animal/Disease Models: Adult male Wistar rat (200-225 g) [7]
Doses: 10 mg/kg
Route of Administration: IV; chemical [8]. Twice a week for 3 weeks
Experimental Results:Reversal of established pH, thereby normalizing pulmonary artery pressure values and vascular structure. \n

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\nInfection and Treatments [7]
\nSeventy animals were equally randomized into five groups: SAL = uninfected and untreated; INF = infected and untreated; SR5, SR10, and SR20 = infected and treated with 5, 10, or 20 mg/kg of the purinergic antagonist suramin . The infection was induced by intraperitoneal inoculation of 5000 T. cruzi trypomastigotes (Y strain). The parasites were obtained from mice previously infected with metacyclic trypomastigotes obtained from late stationary-phase cultures on liver infusion tryptose medium. The doses of suramin were based on (i) one-fourth, (ii) half, and (iii) the therapeutic dose (Sur, 20 mg/kg/day) for African trypanosomiasis. Suramin was dissolved in sterilized water and intraperitoneally administered for 15 consecutive days after confirmation of the infection by microscopic identification of parasites in blood samples from all inoculated mice. Control mice were concurrently treated with sterilized water. The animals were euthanized 48 h after the last treatment by cardiac puncture after deep anesthesia (ketamine 45 mg/kg and xylazine 5 mg/kg, i.p.).\n

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\nTreatment of animals with suramin [8]
\nFor all experiments, adult male Wistar rats (200-225 g) were used. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/Kg). Assessment of pulmonary hypertension was performed as previously described. Briefly, a polyvinyl catheter was introduced into the right jugular vein, then pushed through the RV into the pulmonary artery. A polyethylene catheter was inserted into the right carotid artery. PAP and systemic artery pressure were measured, the thorax was opened, and the left lung was immediately removed and frozen in liquid nitrogen. The heart was dissected and weighed for calculation of the RV hypertrophy index (RV/[LV + S]). The right lung was fixed in the distended state with formalin buffer. After routine processing and paraffin embedding, multiple sections from each lobe were stained with H&E. In each rat, 60 intra-acinar arteries were examined and categorized as nonmuscular (NM), partially muscular (PM), fully muscular (FM), or obliterated (FM+). [8]
\nTo assess the potential preventive and curative effects of suramin , rats were randomly divided into four groups after MCT injection. In the preventive strategy, the treatment was started on the first day, and one group received 10 mg/kg suramin intravenously twice weekly for 3 weeks, while a second group received only the vehicle at the same time points. To assess the potential curative effects of suramin, rats were given MCT and were left untreated for 21 days before being randomly divided into two groups that were subsequently treated with either suramin or vehicle from day 21 to day 42 inclusive. The effect of suramin on survival was evaluated from the day 21 of MCT injection to day 42 corresponding to the treatment period.

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\nAnimal model: Ten-week-old male C57BL/6 mice were used. [7]
\nInfection: Mice were infected by intraperitoneal inoculation of 5000 _T. cruzi_ trypomastigotes (Y strain). [7]
\nTreatment groups: 1) SAL: uninfected control. 2) INF: infected, untreated. 3) SR5, SR10, SR20: infected and treated with 5, 10, or 20 mg/kg Suramin, respectively. Doses were selected based on fractions of the therapeutic dose (20 mg/kg/day) used for African trypanosomiasis. [7]
\nDrug formulation and administration: Suramin was dissolved in sterilized water. It was administered intraperitoneally for 15 consecutive days, starting after confirmation of infection (microscopic identification of parasites in blood). Control mice received sterilized water. [7]
\nEuthanasia and sample collection: Animals were euthanized 48 hours after the last treatment by cardiac puncture under deep anesthesia (ketamine 45 mg/kg and xylazine 5 mg/kg, intraperitoneal). Heart and blood samples were collected for analysis. [7]

Absorption, Distribution and Excretion
Poor gastrointestinal absorption.
Metabolism/Metabolites
Almost not metabolized.
Biological Half-Life
Approximately 36 to 60 days.
The high negative charge of suramin hinders its effective cellular uptake, resulting in a significant difference (approximately 200-fold) between its potent biochemical inhibition of RdRp (IC₅₀ ~0.26 µM) and its weaker inhibition of viral replication in cell-based assays (EC₅₀ ~2.9 µM). [5]
The authors believe that future formulations (e.g., glycol-based chitosan nanoparticles) may improve the bioavailability of suramin in lung tissue. [5]

Protein Binding
Approximately 99.7% Human TDLo IV 46 mg/kg/5 weeks - 1 time Sensory organs and special senses: Other: Eye New England Journal of Medicine, 314(1455), 1986 Mouse LD50 IV 620 mg/kg Kidneys, ureters, and bladder: Renal tubular changes (including acute renal failure, acute tubular necrosis) Advances in Pharmacology and Chemotherapy, 15(289), 1978 [PMID:358805] Suramin is known to bind highly to plasma proteins (such as albumin), which may reduce its effective free concentration in circulation.

[1]. Suramin is an active site-directed, reversible, and tight-binding inhibitor of protein-tyrosine phosphatases. J Biol Chem. 1998 May 15;273(20):12281-7.

[2]. Structure-activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem. 2007 Oct;2(10):1419-31.

[3]. Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Structure. 2007 Mar;15(3):377-89.

[4]. Suramin: a potent inhibitor of the reverse transcriptase of RNA tumor viruses. Cancer Lett. 1979 Nov;8(1):9-22.

[5]. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin. Nat Struct Mol Biol. 2021 Mar;28(3):319-325.

[6]. Suramin affects DNA synthesis in HeLa cells by inhibition of DNA polymerases. Cancer Res. 1990 Dec 15;50(24):7754-7.

[7]. Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by EnhancingParasitism, Inflammation, and Reactive Tissue Damage in Trypanosoma cruzi-Infected Mice. Oxid Med Cell Longev. 2018 Sep 30;2018:7385639.

[8]. The beneficial effect of suramin on monocrotaline-induced pulmonary hypertension in rats. PLoS One. 2013 Oct 15;8(10):e77073.

[9]. Suramin and NF449 Are IP5K Inhibitors That Disrupt IP6-mediated Regulation of Cullin RING Ligase and Sensitize Cancer Cells to MLN4924/pevonedistat. J Biol Chem. 2020 Jun 3;jbc.RA120.014375.

Suramin sodium is an organosodium salt, the hexasodium salt of suramin. It is a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of African trypanosomiasis and river blindness. It possesses a variety of pharmacological activities, including anti-nematode, trypanosome, antitumor, angiogenesis inhibitor, apoptosis inhibitor, EC 2.7.11.13 (protein kinase C) inhibitor, GABA receptor antagonist, GABA-gated chloride channel antagonist, purinergic receptor P2 antagonist, and reniform base receptor agonist. It contains the suramin (6-) structure. Suramin sodium is the sodium salt form of suramin, a polysulfated naphthaleneurea compound with potential antitumor activity. Suramin blocks the binding of various growth factors to their receptors, including insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and tumor growth factor-β (TGF-β), thereby inhibiting endothelial cell proliferation and migration. This drug can also inhibit angiogenesis induced by vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF); retroviral reverse transcriptase; G protein uncoupling from receptors; topoisomerase; folate transport; and steroid production. Suramin is a polyanionic compound with an unclear mechanism of action. It is used to treat African trypanosomiasis and has been used clinically in combination with diethylcarbazine to kill adult Onchocerca filariae. (From JAMA Drug Evaluation Yearbook, 1992, p. 1643) It has also been shown to have potent antitumor properties. See also: Suramin (note moved here). Suramin belongs to the phenylurea class of compounds and has the structure urea, where each amino group is replaced by 3-({2-methyl-5-[(4,6,8-trisulfon-1-naphthyl)carbamoyl]phenyl}carbamoyl)phenyl. It activates the RyR1 subtype rynocyanidin receptor channel in rabbit skeletal muscle and the RyR2 subtype in sheep heart, and has been used for over 100 years to treat human trypanosomiasis. It has multiple functions, including acting as a rynocyanidin receptor agonist, GABA-gated chloride channel antagonist, GABA antagonist, apoptosis inhibitor, antitumor drug, angiogenesis inhibitor, purinergic receptor P2 antagonist, EC 2.7.11.13 (protein kinase C) inhibitor, antinematode, and trypanosome killing agent. It belongs to the phenylurea, secondary amide, and naphthalenesulfonic acid classes. Its function is related to naphthalene-1,3,5-trisulfonic acid. It is the conjugate acid of suramin (6-). It is a polyanionic compound with an unknown mechanism of action. It is used to treat African trypanosomiasis and has been clinically used in combination with diethylcarbazine to kill adult Onchocerca filariae. (Excerpt from JAMA Drug Evaluation Yearbook, 1992, p. 1643) It has also been shown to have potent antitumor properties. Suramin is manufactured by Bayer AG in Germany and marketed under the brand name Germanin®. It has been reported to be found in Strychnos spinosa, with relevant data available. Suramin is a polysulfated naphthalene urea compound with potential antitumor activity. It blocks the binding of various growth factors to their receptors, including insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and tumor growth factor-β (TGF-β), thereby inhibiting endothelial cell proliferation and migration. This drug also inhibits vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)-induced angiogenesis; retroviral reverse transcriptase; G protein uncoupling from receptors; topoisomerase; folate transport; and steroid production. (NCI04) A polyanionic compound with an unknown mechanism of action. It is used to treat African trypanosomiasis and has been clinically used in combination with diethylcarbazine to kill adult Onchocerca filariae. (Excerpted from JAMA Drug Evaluation Yearbook, 1992, p. 1643) It has also been shown to possess potent antitumor properties. Drug Indications For the treatment of human sleeping sickness, onchocerciasis, and other diseases caused by trypanosomes and worms. Mechanism of Action Its mechanism of action is unclear, but its trypanolytic activity may be attributed to the inhibition of enzymes involved in the oxidation of reduced nicotinamide adenine dinucleotide (NADH). NADH acts as a coenzyme in many cellular responses of trypanosome parasites, such as respiration and glycolysis. Suramin's role in treating onchocerciasis is to kill adult worms and partially kill microfilariae. It may also act as an antagonist of the P2 receptor and an agonist of the ranitidine receptor. Furthermore, it inhibits the follicle-stimulating hormone receptor. Suramin is a well-known antitrypsy drug that has been found to strongly inhibit the RNA-directed DNA polymerase (reverse transcriptase) activity of various onchocerciasis viruses, such as Moloney murine leukemia virus, Rasheed murine leukemia virus, Moloney murine sarcoma virus, and avian myeloblastoma virus. Inhibition of enzyme activity was observed using both endogenous viral RNA and (A)n·oligo(dT) as template primers. Suramin achieved a 50% inhibition rate of reverse transcriptase activity against trypanosome viruses at concentrations of 0.1–1 μg/mL. In this respect, it is superior to another trypanolytic agent, ethidium bromide, which is considered one of the most effective inhibitors of trypanosome virus DNA polymerase. The inhibitory effect of suramin on reverse transcriptase activity is competitive with the template primer (A)n·oligo(dT), suggesting that the drug may interact with the template primer binding site of the enzyme. [4]

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Inositol hexaphosphate (IP6) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentaphosphate (IP5) under the action of a single IP5 2-kinase (IP5K). Genetic and biochemical studies have shown that IP6 usually acts as a structural cofactor of proteins, participating in processes such as mRNA export, DNA repair, necrosis and apoptosis, three-dimensional genome organization, HIV infection, and cullin-RING ligase (CRL) deubiquitination. However, it is unclear whether pharmacological perturbations of intracellular IP6 levels affect these processes. In this study, small molecules that can regulate human IP5K activity were screened, and it was found that the antiparasitic drug and the polysulfated compound suramin could effectively inhibit IP5K activity in vitro and in vivo. Molecular docking experiments and biochemical verification results showed that suramin targets IP5K in a unique bidentate coordination manner, while binding to both ATP and IP5 binding pockets, thereby inhibiting IP5 phosphorylation and ATP hydrolysis. NF449 is a suramin analog with an additional sulfonic acid group, which has a stronger ability to inhibit IP5K activity. Both suramin and NF449 can disrupt the IP6-dependent isolation of the CRL by the de-NEDDylation enzyme COP9 signaling body, thereby affecting the CRL activity cycle and component dynamics in an IP5K-dependent manner. In addition, non-toxic doses of suramin, NF449 or NF110 exacerbate the cell viability decrease induced by NEDDylation inhibitors and the clinical trial drug MLN4924/pevonedistat, suggesting a synergistic effect. Suramin and its analogues provide structural templates for designing highly effective and specific IP5K inhibitors that can be used in combination with MLN4924/pevonedistat for treatment. IP5K is a potential target of suramin's mechanism of action, explaining the therapeutic effect of suramin. [9] Suramin (hexasodium salt) is a polysulfated naphthalene urea compound that has historically been used to treat trypanosomiasis and onchocerciasis.
Because it can interfere with growth factor-receptor interactions (e.g., PDGF, EGF, bFGF) and inhibit various enzymes, it has been studied as an experimental antitumor drug.
This study provides a mechanistic explanation for the increased tyrosine phosphorylation levels of cellular proteins observed after suramin treatment of cancer cells, namely, through direct competitive inhibition of the active site of PTPase.
The structural similarity between the aryl sulfonic acid group of suramin and phosphotyrosine is considered the basis for its competitive inhibition of PTPase.

C51H34N6NA6O23S6

1429.17

1427.938

C, 42.86; H, 2.40; N, 5.88; Na, 9.65; O, 25.75; S, 13.46

129-46-4

Suramin;145-63-1

8514

Typically exists as Off-white to light brown solid at room temperature

11.61

6

23

10

92

2940

0

O=C(NC1=CC(C(NC2=CC(C(NC3=CC=C(S(=O)([O-])=O)C4=CC(S(=O)([O-])=O)=CC(S(=O)([O-])=O)=C34)=O)=CC=C2C)=O)=CC=C1)NC5=CC(C(NC6=CC(C(NC7=CC=C(S(=O)([O-])=O)C8=CC(S(=O)([O-])=O)=CC(S(=O)([O-])=O)=C78)=O)=CC=C6C)=O)=CC=C5.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]

VAPNKLKDKUDFHK-UHFFFAOYSA-H

InChI=1S/C51H40N6O23S6.6Na/c1-25-9-11-29(49(60)54-37-13-15-41(83(69,70)71)35-21-33(81(63,64)65)23-43(45(35)37)85(75,76)77)19-39(25)56-47(58)27-5-3-7-31(17-27)52-51(62)53-32-8-4-6-28(18-32)48(59)57-40-20-30(12-10-26(40)2)50(61)55-38-14-16-42(84(72,73)74)36-22-34(82(66,67)68)24-44(46(36)38)86(78,79)80;;;;;;/h3-24H,1-2H3,(H,54,60)(H,55,61)(H,56,58)(H,57,59)(H2,52,53,62)(H,63,64,65)(H,66,67,68)(H,69,70,71)(H,72,73,74)(H,75,76,77)(H,78,79,80);;;;;;/q;6*+1/p-6

sodium 8,8'-((3,3'-((3,3'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))bis(4-methylbenzoyl))bis(azanediyl))bis(naphthalene-1,3,5-trisulfonate)

NSC-34936l; NSC34936 ; NSC 34936;Suramin Hexasodium; BAY 205; BAY-205; BAY205; Germanin; NF 060; NF-060; NF060; Suramin; Farma; Fourneau; 129-46-4; suramin hexasodium salt; Suramin sodium salt; Antrypol; Germanin; Naganin;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~83.33 mg/mL (~58.31 mM)
H2O : ~50 mg/mL (~34.99 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (1.46 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (1.46 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 100 mg/mL (69.97 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)