The Experts below are selected from a list of 12870 Experts worldwide ranked by ideXlab platform
Shougang Zhuang - One of the best experts on this subject based on the ideXlab platform.
-
Suramin inhibits the development and progression of peritoneal fibrosis
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Chongxiang Xiong, Lu Fang, Shougang ZhuangAbstract:Peritoneal fibrosis is one of the most serious complications in patients with peritoneal dialysis (PD) and is associated with the loss of peritoneal membrane ultrafiltration function. In this study, we investigated whether Suramin, an inhibitor that blocks multiple growth factors by binding to their receptors, would prevent development of peritoneal fibrosis in a rat model. Rats were given a daily intraperitoneal injection of chlorhexidine gluconate (CG) for 3 weeks to induce peritoneal fibrosis. Administration of Suramin at 5, 10, and 20 mg/kg dose-dependently attenuated peritoneal membrane thickening and expression of collagen I, fibronectin, and α-smooth muscle actin. Increased expression of transforming growth factor-β1 (TGF-β1) and phosphorylation of Smad3 was detected in fibrotic peritoneum and inhibited by Suramin treatment. Suramin was also effective in blocking CG-induced phosphorylation of inhibitor of κB (IκB) and nuclear factor (NF)-κBp65, expression of several inflammatory cytokines, and infiltration of macrophages in the peritoneum. Moreover, Suramin suppressed angiogenesis and expression of vascular endothelial growth factor, a molecule associated with angiogenesis in the injured peritoneum. Therefore, our results indicate that Suramin treatment can effectively alleviate the development of peritoneal fibrosis by suppression of TGF-β1 signaling, inflammation, and angiogenesis, and suggest that Suramin may have therapeutic potential for prevention of peritoneal fibrosis in PD patients.
-
Suramin alleviates glomerular injury and inflammation in the remnant kidney
PLOS ONE, 2012Co-Authors: Song He, Evelyn Tolbert, Shougang Zhuang, Rujun Gong, George BaylissAbstract:Background Recently, we demonstrated that Suramin, a compound that inhibits the interaction of multiple cytokines/growth factors with their receptors, inhibits activation and proliferation of renal interstitial fibroblasts, and attenuates the development of renal interstitial fibrosis in the murine model of unilateral ureteral obstruction (UUO). However, it remains unclear whether Suramin can alleviate glomerular and vascular lesions, which are not typical pathological changes in the UUO model. So we tested the efficacy of Suramin in the remnant kidney after 5/6 nephrectomy, a model characterized by the slow development of glomerulosclerosis, vascular sclerosis, tubulointerstitial fibrosis and renal inflammation, mimicking human disease. Methods/Findings 5/6 of normal renal mass was surgically ablated in male rats. On the second week after surgery, rats were randomly divided into Suramin treatment and non-treatment groups. Suramin was given at 10 mg/kg once per week for two weeks. In the remnant kidney of mice receiving Suramin, glomerulosclerosis and vascular sclerosis as well as inflammation were ameliorated. Suramin also attenuated tubular expression of two chemokines, monocyte chemoattractant protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). After renal mass ablation, several intracellular molecules associated with renal fibrosis, including NF-kappaB p65, Smad-3, signal transducer and activator of transcription-3 and extracellular regulated kinase 1/2, are phosphorylated; Suramin treatment inhibited their phosphorylation. Futhermore, Suramin abolished renal ablation-induced phosphorylation of epidermal growth factor receptor and platelet derived growth factor receptor, two receptors that mediate renal fibrosis. Conclusions and Significance These findings suggest that Suramin attenuates glomerular and vascular injury and reduces inflammatory responses by suppression of multiple growth factor receptor-mediated profibrotic signaling pathways. Therefore, Suramin may be a useful drug in preventing the fibrosis and sclerosis that characterizes progression of chronic kidney disease.
-
delayed administration of Suramin attenuates the progression of renal fibrosis in obstructive nephropathy
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Evelyn Tolbert, Murugavel Ponnusamy, Shougang ZhuangAbstract:We recently showed that Suramin treatment prevents the onset of renal fibrosis in a model of obstructive nephropathy induced by unilateral ureteral obstruction (UUO). In this study, we further assessed the effect of delayed administration of Suramin on the progression of tubulointerstitial fibrosis. Mice were given a single dose of Suramin at 20 mg/kg starting at day 3 of obstruction, and kidneys were harvested after an additional 7 or 14 days of obstruction. Suramin completely blocked further increase in expression of type I collagen and fibronectin and largely suppressed expression of α-smooth muscle actin (α-SMA) in both treatment groups. UUO injury induced phosphorylation of Smad-3, a key mediator of transforming growth factor-β (TGF-β) signaling, epidermal growth factor receptor, and platelet-derived growth factor receptor after 3 days and further increased at 10 days after UUO injury. When Suramin was administered at 3 days after obstruction, phosphorylation of these molecules was not further increased in the obstructed kidney. Suramin treatment also inhibited activation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1 and 2, two signaling pathways associated with renal fibrogenesis. Furthermore, delayed application of Suramin suppressed TGF-β1-induced expression of α-SMA and fibronectin in cultured renal interstitial fibroblasts. These results indicate that administration of Suramin is effective in attenuating the progression of renal fibrosis after injury and suggest the potential clinical application of Suramin as an antifibrotic treatment in patients with chronic kidney disease.
-
Suramin inhibits renal fibrosis in chronic kidney disease
Journal of The American Society of Nephrology, 2011Co-Authors: Evelyn Tolbert, Maoyin Pang, Murugavel Ponnusamy, Shougang ZhuangAbstract:The activation of cytokine and growth factor receptors associates with the development and progression of renal fibrosis. Suramin is a compound that inhibits the interaction of several cytokines and growth factors with their receptors, but whether Suramin inhibits the progression of renal fibrosis is unknown. Here, treatment of cultured renal interstitial fibroblasts with Suramin inhibited their activation induced by TGF-β1 and serum. In a mouse model of obstructive nephropathy, administration of a single dose of Suramin immediately after ureteral obstruction abolished the expression of fibronectin, largely suppressed expression of α-SMA and type I collagen, and reduced the deposition of extracellular matrix proteins. Suramin also decreased the expression of multiple cytokines including TGF-β1 and reduced the interstitial infiltration of leukocytes. Moreover, Suramin decreased expression of the type II TGF-β receptor, blocked phosphorylation of the EGF and PDGF receptors, and inactivated several signaling pathways associated with the progression of renal fibrosis. In a rat model of CKD, Suramin abrogated proteinuria, limited the decline of renal function, and prevented glomerular and tubulointerstitial damage. Collectively, these findings indicate that Suramin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.
Charles E Myers - One of the best experts on this subject based on the ideXlab platform.
-
antitumor activity of Suramin in hormone refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables
Cancer, 1995Co-Authors: Nancy A. Dawson, Seth M. Steinberg, Donna Headlee, William D. Figg, Charles E Myers, Michael R. Cooper, Alain Thibault, Raymond C Bergan, Edward A Sausville, Oliver SartorAbstract:Background. A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided Suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. Methods. Fifty-four patients whose disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose disease progressed on hydrocortisone received Suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for Suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of Suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma Suramin concentrations between 300-175 ρg/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and soft-tissue disease response. Results. Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/ or a partial response of measurable soft-tissue disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to Suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no soft-tissue disease responses to Suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for Suramin therapy. The median survival for all patients was 14.6 months. Conclusion. Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeatic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of Suramin. Cancer 1995; 76:453–62.
-
Adaptive control with feedback strategies for Suramin dosing
Clinical Pharmacology & Therapeutics, 1992Co-Authors: Michael R. Cooper, Donna Headlee, Ronald Lieberman, Renato V. La Rocca, Paige R Gernt, Maribeth S Weinberger, David R. Kohler, Barry R. Goldspiel, Carl C. Peck, Charles E MyersAbstract:Suramin, a drug used in the treatment of parasitic diseases, is currently being evaluated in clinical trials as an antineoplastic agent. The use of therapeutic drug monitoring and adaptive control with feedback in clinical trials of Suramin was initially motivated by an association between acute neurologic toxicity and plasma Suramin concentrations in excess of 350 μg/ml. We have prospectively examined the performance of both two- and three-compartment population pharmacokinetic models in controlling plasma Suramin concentrations and have found that a three-compartment model best describes this drug. No correlation was found between the clearance of Suramin and creatinine clearance, as had been previously hypothesized. The low systemic clearance of Suramin and the number of parameters required to describe the three-compartment model suggest the need for a bayesian approach to the estimation of individual pharmacokinetics. Clinical Pharmacology and Therapeutics (1992) 52, 11–23; doi:10.1038/clpt.1992.97
-
The effect of Suramin on laboratory tests of coagulation.
Thrombosis and Haemostasis, 1992Co-Authors: Mcdonald K. Horne, Michael R. Cooper, Olga J. Wilson, Harvey R. Gralnick, Charles E MyersAbstract:Abstract The antitrypanosomal drug Suramin, which has recently been under investigation as a cancer chemotherapeutic agent, has previously been found to induce heparin-like anticoagulants in treated patients. In the currently reported work Suramin is shown to have an additional anticoagulant activity that is due to direct effects of the drug on procoagulant proteins. The studies were conducted with pooled normal plasma treated in vitro with Suramin and with plasma samples obtained from patients who had received the drug intravenously for 2 weeks. It is demonstrated that in plasma Suramin inhibits factors V, VIII, IX, X, XI, and XII, while thrombin, prothrombin, and factor VII are unaffected. The inhibition of factor V is virtually irreversible, although the effect of Suramin on the other factors is readily reversed by dilution.
-
Suramin-Induced Skin Reactions
Archives of Dermatology, 1992Co-Authors: Brian Patrick O’donnell, Nancy A. Dawson, Charles E Myers, Raymond B. Weiss, William D. JamesAbstract:Background and Design.— Suramin sodium, a polysulfonated naphthylurea, has been used for more than 70 years as a chemotherapeutic agent for a variety of diseases. In a phase II trial of Suramin, 20 patients with metastatic prostate carcinoma refractory to hormonal manipulation were evaluated retrospectively for evidence of skin toxicity. Results.— Three types of skin reaction were noted: generalized, erythematous, maculopapular eruption (10 patients); keratoacanthoma (two patients); and disseminated superficial actinic porokeratosis (one patient). A total of 15 episodes of some form of skin reaction occurred in 13 patients. The maculopapular eruptions resolved in 3 to 5 days despite continued treatment wtih Suramin. Conclusions.— Cutaneous toxicity was a frequent and, often, self-limited side effect of Suramin therapy, occurring in 13 (65%) patients. Keratoacanthoma and disseminated superficial actinic porokeratosis have not previously been reported to occur with Suramin therapy. The immunosuppressive effect of Suramin may induce the keratoacanthoma and disseminated superficial actinic porokeratosis lesions. ( Arch Dermatol. 1992;128:75-79)
-
effect of Suramin on human prostate cancer cells in vitro
The Journal of Urology, 1991Co-Authors: Renato V. La Rocca, Michael R. Cooper, Romano Danesi, Carlos A Jamisdow, Winnann M Ewing, Marston W Linehan, Charles E MyersAbstract:Abstract Suramin, a polyanionic compound with known antiparasitic activity, has been shown to be adrenocorticolytic in primates and to have clinical efficacy in the treatment of patients with metastatic prostate cancer refractory to conventional hormonal manipulation. To better characterize the activity of Suramin on prostate cancer biology, we studied the effect of the drug on plasma adrenal androgens of patients and on the human prostate adenocarcinoma cell lines PC-3, DU 145 and LNCaP-FGC. Five cancer patients treated with Suramin had an approximate 40% decline in circulating androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate levels. The drug inhibited the colony formation in two of the three cell lines at concentrations clinically achievable in humans without excessive drug-related toxicity. The presence of Suramin 300 μg./ml. partially inhibited the growth stimulatory effect of testosterone and basic fibroblast growth factor, but not that of epidermal growth factor. The cellular concentration of Suramin following exposure to a single dose increases linearly over time in each of the cell lines with LNCaP-FGC accumulating the highest levels of the drug; cellular levels of Suramin, not androgen or growth factor sensitivity, correlated with the sensitivity to the drug. The concentrations of prostatic acid phosphatase and prostatic specific antigen released by LNCaP-FGC cells in cell culture medium declined in the presence of increasing levels of Suramin in a manner which exceeded the decrease in cell number. We conclude that Suramin, aside from decreasing circulating androgens through its adrenocorticolytic effect, is also capable exerting a direct inhibitory effect on cell proliferation of prostate cancer cells, and interfere at a cellular level with the growth stimulatory effects of exogenous testosterone and basic fibroblast growth factor.
Peter Nickel - One of the best experts on this subject based on the ideXlab platform.
-
Angiostatic effects of Suramin analogs in vitro.
Anti-Cancer Drugs, 2000Co-Authors: Angela Firsching-hauck, Peter Nickel, Claudia Yahya, Carla Wandt, Renate Kulik, Nicola Simon, Martina Zink, Volker Nehls, Bruno AllolioAbstract:Suramin analogs are polyanionic naphthylureas structurally related to Suramin, an antitumor agent with a narrow therapeutic window. The angiostatic activities of Suramin and 16 Suramin analogs were investigated using an easily quantifiable in vitro angiogenesis system. In addition, the antiproliferative activities of the analogs were studied in four different human tumor cell lines and in porcine aortic endothelial cells. The Suramin analogs encompassed two main structural variations, i.e. their molecular size, and the number and substitution pattern of the sulfonate groups. Some Suramin analogs with a reduced number of sulfonate groups (NF062, NF289 and NF326) showed significant dose-dependent angiostatic and also antiproliferative activities. The disulfonate NF062 was superior to Suramin in inhibiting HT29 and T47D tumor cells while demonstrating a similar angiostatic potential as Suramin. Therefore, the sulfonate groups in the para position of the amino groups of the naphthyl residues of Suramin seem to be of special importance. The very small disulfonates (NF108, NF109, NF499, NF500 and NF241) and the asymmetric compound NF520, one half of the Suramin molecule, are inactive. Therefore, a minimal molecule size seems to be essential for the biological activity. Suramin is a rather rigid molecule. The highly flexible analogs (NF527, NF528 and NF529) are inactive. This indicates that the molecular rigidity is important for the biological activity.
-
Stability of Suramin in aqueous solution; possible implications for the search for Suramin metabolites in patients.
Archiv Der Pharmazie, 1996Co-Authors: Matthias U Kassack, Peter NickelAbstract:The stability of an aqueous solution of Suramin has been determined. The only degradation product detectable by HPLC was the amine precursor 2. The decomposition kinetics of Suramin at different temperatures are shown. Because of first order kinetics the Arrhenius equation could not be used to evaluate the decomposition data. A good correlation was obtained between the reaction constants and the temperature (r = 0.9898). After 42 days at 37 degrees C, 2 % of Suramin are hydrolysed. Possible implications of our results for the search for Suramin metabolites in patients are discussed.
-
Inhibition of Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Activity by Suramin and Suramin Analogues Is Correlated to Interaction with the GM-CSF Nucleotide-binding Site
Cancer Research, 1995Co-Authors: Michael A. Doukas, Ashok J. Chavan, Cecelia Gass, Peter Nickel, Thomas C. Boone, Boyd E. HaleyAbstract:Suramin and Suramin analogues strongly inhibit both nucleotide interaction with the nucleotide-binding site of granulocyte-macrophage colony-stimulating factor (GM-CSF) and bioactivity of the molecule as assessed by competition photoaffinity labeling and cell proliferation assay, respectively. The half-maximal inhibition of cell proliferation by Suramin occurs at 68 ± 2.5 µm; three Suramin analogues achieved comparable activity. The degree of competitive inhibition of nucleotide-binding by these compounds and the inhibition of GM-CSF bioactivity are correlated such that the compounds show similar rank-order by both of these methods. The strong interaction of Suramin and related compounds with the nucleotide-binding site may mimic nucleotide-mediated inhibition of GM-CSF bioactivity and may be an important mechanism by which Suramin acts as a pharmacological anti-growth factor agent.
-
antiproliferative and angiostatic activity of Suramin analogues
Cancer Research, 1995Co-Authors: Angela Firsching, Peter Nickel, P Mora, Bruno AllolioAbstract:Abstract Suramin, a polyanionic naphthylurea, represents a novel class of antineoplastic drugs with a variety of activities against tumor cell proliferation. However, its clinical use is hampered by serious toxicity. To gain more insight into structure-activity relationships of Suramin, we investigated the antiproliferative action of Suramin and 19 Suramin analogues in vitro using 5 different human cell lines (HT29, MCF7, SW13, PC3, and T47D). In addition, for seven analogues the angiostatic potential with and without hydrocortisone was assessed using a modified chorioallantois membrane assay. Only the symmetric compounds exhibited antiproliferative action in vitro; several analogues were more active than Suramin (e.g., NF031, NF037, NF326). Suramin analogues with six sulfonic acid groups showed a wide range of activity in HT29 cells (IC50 = 43–390 µm), indicating that besides the polyanionic feature, other structural elements are important (e.g., stiffness of the bridge between the two terminal naphthyl rings). Some of the smaller ureas with only four sulfonic acid groups retained significant antiproliferative activity. Compounds active in cell lines also inhibited angiogenesis in the chorioallantois membrane assay, suggesting a similar mode of action. Hydrocortisone increased the angiostatic effect of most but not all of the screened Suramin analogues. These findings may guide the use of Suramin analogues for improved antitumor therapy in vivo.
-
Suramin inhibits binding of the v3 region of hiv 1 envelope glycoprotein gp120 to galactosylceramide the receptor for hiv 1 gp120 on human colon epithelial cells
Journal of Biological Chemistry, 1994Co-Authors: Nouara Yahi, Peter Nickel, Jeanmarc Sabatier, Kamel Mabrouk, Francisco Gonzalezscarano, Jacques FantiniAbstract:Abstract The infection of human colonic epithelial cells HT-29 by human immunodeficiency virus type 1 (HIV-1) occurs independently of CD4, the main HIV-1 receptor expressed on lymphocytes and macrophages. Recent studies from our group have shown that HT-29 cells express the glycosphingolipid galactosylceramide (GalCer), a potential alternative receptor for the HIV-1 envelope glycoprotein gp120. The binding of recombinant gp120 to GalCer was blocked by monoclonal antibodies directed against the third variable region (V3) of gp120, suggesting that the V3 domain was implicated in GalCer recognition. In the present report, we show that Suramin, a polysulfonyl naphtylurea known to inhibit retroviral reverse transcriptases in vitro, blocks HIV-1 infection in HT-29 cells. The effect is dose dependent, with a half-maximal inhibition (IC50) achieved for a Suramin concentration of 54 micrograms/ml. Since [3H]Suramin was not significantly internalized into HT-29 cells during our infection assay (i.e. 2 h), we have considered the possibility that the drug could act at an extracellular step of the HIV-1 cycle. Using a high performance thin layer chromatography binding assay, we show that Suramin inhibits binding of HIV-1 gp120 to purified GalCer with an IC50 of 25 micrograms/ml. Suramin does not bind to GalCer, since preincubation of GalCer with Suramin did not prevent the subsequent attachment of gp120. Using a solid-phase assay, we show that [3H]Suramin specifically binds to recombinant gp120 and that this binding could be blocked by a monoclonal antibody specific for the conserved GPGRAF motif of the V3 domain of gp120. We also demonstrate that [3H]Suramin binds to multibranched synthetic GPGRAF peptides that block HIV-1 infection in HT-29 cells. Binding of [3H]Suramin to V3 peptides is specific and inhibited by unlabeled Suramin (IC50 of 28 micrograms/ml). In contrast, the Suramin derivative NF036, that is unable to block HIV-1 infection in HT-29 cells, does not inhibit the binding of [3H]Suramin to V3 peptides. Taken together, these results suggest that Suramin blocks HIV-1 infection in HT-29 cells because it binds to the V3 domain of gp120 and hence prevents the interaction between gp120 and the GalCer receptor.
Jacques Fantini - One of the best experts on this subject based on the ideXlab platform.
-
Co-localization of Suramin and serum albumin in lysosomes of Suramin-treated human colon cancer cells.
Cancer Letters, 1996Co-Authors: Stephen Baghdiguian, Jeanne-andrée Boudier, Jacques FantiniAbstract:Abstract Suramin is a polysulfonated compound currently under investigation for the treatment of various types of cancer. Pharmacokinetic studies from clinical trials in humans have shown that most of the circulating drug is associated with serum albumin. The objective of the present study was to investigate the intracellular localization of Suramin and serum albumin in human colon cancer cells (HT-29-D4) upon Suramin treatment. For this purpose, combined gold labeling and autoradiographic methods were performed on HT-29-D4 cells grown in serum free medium containing both [3H]Suramin and colloidal goldalbumin. These morphological experiments demonstrated for the first time that Suramin and serum albumin were co-localized in the same cellular compartment (i.e. the lysosomal system) of the Suramin-treated HT-29-D4 cells. The albumin-directed targeting of Suramin in lysosomes may allow the drug to inhibit the activity of several lysosomal hydrolases. resulting in a lysosomal storage disorder.
-
Suramin inhibits binding of the v3 region of hiv 1 envelope glycoprotein gp120 to galactosylceramide the receptor for hiv 1 gp120 on human colon epithelial cells
Journal of Biological Chemistry, 1994Co-Authors: Nouara Yahi, Peter Nickel, Jeanmarc Sabatier, Kamel Mabrouk, Francisco Gonzalezscarano, Jacques FantiniAbstract:Abstract The infection of human colonic epithelial cells HT-29 by human immunodeficiency virus type 1 (HIV-1) occurs independently of CD4, the main HIV-1 receptor expressed on lymphocytes and macrophages. Recent studies from our group have shown that HT-29 cells express the glycosphingolipid galactosylceramide (GalCer), a potential alternative receptor for the HIV-1 envelope glycoprotein gp120. The binding of recombinant gp120 to GalCer was blocked by monoclonal antibodies directed against the third variable region (V3) of gp120, suggesting that the V3 domain was implicated in GalCer recognition. In the present report, we show that Suramin, a polysulfonyl naphtylurea known to inhibit retroviral reverse transcriptases in vitro, blocks HIV-1 infection in HT-29 cells. The effect is dose dependent, with a half-maximal inhibition (IC50) achieved for a Suramin concentration of 54 micrograms/ml. Since [3H]Suramin was not significantly internalized into HT-29 cells during our infection assay (i.e. 2 h), we have considered the possibility that the drug could act at an extracellular step of the HIV-1 cycle. Using a high performance thin layer chromatography binding assay, we show that Suramin inhibits binding of HIV-1 gp120 to purified GalCer with an IC50 of 25 micrograms/ml. Suramin does not bind to GalCer, since preincubation of GalCer with Suramin did not prevent the subsequent attachment of gp120. Using a solid-phase assay, we show that [3H]Suramin specifically binds to recombinant gp120 and that this binding could be blocked by a monoclonal antibody specific for the conserved GPGRAF motif of the V3 domain of gp120. We also demonstrate that [3H]Suramin binds to multibranched synthetic GPGRAF peptides that block HIV-1 infection in HT-29 cells. Binding of [3H]Suramin to V3 peptides is specific and inhibited by unlabeled Suramin (IC50 of 28 micrograms/ml). In contrast, the Suramin derivative NF036, that is unable to block HIV-1 infection in HT-29 cells, does not inhibit the binding of [3H]Suramin to V3 peptides. Taken together, these results suggest that Suramin blocks HIV-1 infection in HT-29 cells because it binds to the V3 domain of gp120 and hence prevents the interaction between gp120 and the GalCer receptor.
Jian Li - One of the best experts on this subject based on the ideXlab platform.
-
the approved pediatric drug Suramin identified as a clinical candidate for the treatment of ev71 infection Suramin inhibits ev71 infection in vitro and in vivo
Emerging microbes & infections, 2014Co-Authors: Benjamin Bailly, Fernando Arenzanaseisdedos, Shanshan Xu, Mei Zeng, Xinsheng Chen, Liang Shen, Ying Zhang, Patrice Guillon, Philippe Buchy, Jian LiAbstract:Enterovirus 71 (EV71) causes severe central nervous system infections, leading to cardiopulmonary complications and death in young children. There is an urgent unmet medical need for new pharmaceutical agents to control EV71 infections. Using a multidisciplinary approach, we found that the approved pediatric antiparasitic drug Suramin blocked EV71 infectivity by a novel mechanism of action that involves binding of the naphtalentrisulonic acid group of Suramin to the viral capsid. Moreover, we demonstrate that when Suramin is used in vivo at doses equivalent to or lower than the highest dose already used in humans, it significantly decreased mortality in mice challenged with a lethal dose of EV71 and peak viral load in adult rhesus monkeys. Thus, Suramin inhibits EV71 infection by neutralizing virus particles prior to cell attachment. Consequently, these findings identify Suramin as a clinical candidate for further development as a therapeutic or prophylactic treatment for severe EV71 infection.
