Risuteganib
目录号 : GC37541An anti-integrin peptide
Cas No.:1307293-62-4
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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Risuteganib is an anti-integrin peptide and a derivative of RGD peptide .1 Risuteganib (400 ?M) protects against hydroquinone-induced necrosis and apoptosis, as well as inhibits hydroquinone-induced production of reactive oxygen species (ROS), in human retinal pigment epithelial (RPE) cells.2 It decreases the expression of BAX, VEGFA, and ITB1 in human age-related macular degeneration (AMD) cybrid cell lines when used at a concentration of 20 mg/ml.3 Risuteganib arrests aberrant blood vessel growth mediated by αVβ3, αVβ5, and α5β1 integrins in vivo.1
1.Kaiser, P., Boyer, D.D., Campochiaro, P.A., et al.Integrin peptide therapy: The first wet AMD experienceInvest. Opth. Vis. Sci.54(15)2177(2013) 2.Yang, P., Shao, Z., Besley, N.A., et al.Risuteganib protects against hydroquinone-induced injury in human RPE cellsInvest. Ophthalmol. Vis. Sci.61(10)35(2020) 3.Differential effects of risuteganib and bevacizumab on AMD cybrid cellsExp. Eye Res.203108287(2021)
Cas No. | 1307293-62-4 | SDF | |
分子式 | C22H39N9O11S | 分子量 | 637.66 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.5682 mL | 7.8412 mL | 15.6823 mL |
5 mM | 0.3136 mL | 1.5682 mL | 3.1365 mL |
10 mM | 0.1568 mL | 0.7841 mL | 1.5682 mL |
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Risuteganib-a novel integrin inhibitor for the treatment of non-exudative (dry) age-related macular degeneration and diabetic macular edema
Expert Opin Investig Drugs 2020 Jun;29(6):547-554.PMID:32349559DOI:10.1080/13543784.2020.1763953.
Introduction: Non-exudative (dry) age-related macular degeneration (AMD) and diabetic macular edema (DME) are leading causes of vision loss worldwide. Besides age-related eye disease study (AREDS) vitamin supplements, there are no efficacious pharmaceutical interventions for dry AMD available. While numerous pharmacologics are available to treat diabetic macular edema (DME), many patients respond suboptimally to existing therapies. Risuteganib is a novel anti-integrin peptide that targets the multiple integrin heterodimers involved in the pathophysiology of dry AMD and DME. Inhibiting these selected integrin heterodimers may benefit patients with these conditions. Areas covered: This article offers a brief overview of current pharmaceuticals available for dry AMD and DME. The proposed role of integrins in AMD and DME is reviewed and later, Risuteganib, a novel anti-integrin peptide is introduced. The data from initial Phase 1 and Phase 2 Risuteganib clinical trials are discussed in the latter part of the paper. Expert opinion: While there are currently limited treatment options for dry AMD, more data are needed before we can truly evaluate the benefits of adopting Risuteganib into the clinic. Conversely, several effective treatment options exist for DME; hence, Risuteganib must show that it can add to these results, especially in those with refractory disease, before retina specialists adopt Risuteganib into their treatment regimens.
Risuteganib Protects against Hydroquinone-induced Injury in Human RPE Cells
Invest Ophthalmol Vis Sci 2020 Aug 3;61(10):35.PMID:32818234DOI:10.1167/iovs.61.10.35.
Purpose: Cigarette smoking has been implicated in the pathogenesis of AMD. Integrin dysfunctions have been associated with AMD. Herein, we investigate the effect of Risuteganib (RSG), an integrin regulator, on RPE cell injury induced by hydroquinone (HQ), an important oxidant in cigarette smoke. Methods: Cultured human RPE cells were treated with HQ in the presence or absence of RSG. Cell death, mitochondrial respiration, reactive oxygen species production, and mitochondrial membrane potential were measured by flow cytometry, XFe24 analyzer, and fluorescence plate reader, respectively. Whole transcriptome analysis and gene expression were analyzed by Illumina RNA sequencing and quantitative PCR, respectively. F-actin aggregation was visualized with phalloidin. Levels of heme oxygenase-1, P38, and heat shock protein 27 proteins were measured by Western blot. Results: HQ induced necrosis and apoptosis, decreased mitochondrial bioenergetics, increased reactive oxygen species levels, decreased mitochondrial membrane potential, increased F-actin aggregates, and induced phosphorylation of P38 and heat shock protein 27. HQ, but not RSG alone, induced substantial transcriptome changes that were regulated by RSG cotreatment. RSG cotreatment significantly protected against HQ-induced necrosis and apoptosis, prevented HQ-reduced mitochondrial bioenergetics, decreased HQ-induced reactive oxygen species production, improved HQ-disrupted mitochondrial membrane potential, reduced F-actin aggregates, decreased phosphorylation of P38 and heat shock protein 27, and further upregulated HQ-induced heme oxygenase-1 protein levels. Conclusions: RSG has no detectable adverse effects on healthy RPE cells, whereas RSG cotreatment protects against HQ-induced injury, mitochondrial dysfunction, and actin reorganization, suggesting a potential role for RSG therapy to treat retinal diseases such as AMD.
Differential effects of Risuteganib and bevacizumab on AMD cybrid cells
Exp Eye Res 2021 Feb;203:108287.PMID:33075294DOI:10.1016/j.exer.2020.108287.
Purpose: Intravitreal injections of anti-vascular endothelial growth factor (VEGF) treatments are currently used to treat wet age-related macular degeneration (AMD), diabetic retinopathy, and macular edema. Chronic, repetitive treatments with anti-VEGF may have unintended consequences beyond the inhibition of angiogenesis. Most recently, clinical trials have been conducted with Risuteganib (RSG, Luminate®), which is anti-angiogenic and has neuroprotective and anti-inflammatory properties. Mitochondrial damage and dysfunction play a major role in development of AMD. Transmitochondrial cybrids are cell lines established by fusing human retinal pigment epithelial (RPE) cells that are Rho0 (lacking mtDNA) with platelets isolated from AMD subjects or age-matched normal subjects. Cybrid cell lines have identical nuclei but mitochondria from different subjects, enabling investigation of the functional consequences of damaged AMD mitochondria. The present study compares the responses of AMD cybrids treated with bevacizumab (Bmab, Avastin®) versus Risuteganib (RSG, Luminate®). Methods: Cybrids were created by fusing mtDNA depleted ARPE-19 cells with platelets from AMD or age-matched normal patients. AMD (n = 5) and normal (n = 3) cybrids were treated for 48 h with or without 1x clinical dose of 1.25 mg/50 μl (25,000 μg/ml) of Bmab or 1.0 mg/50 μl (20,000 μg/ml) of RSG. Cultures were analyzed for levels of cleaved caspase 3/7 and NucLight Rapid Red staining (IncuCyte® Live Cell Imager), mitochondrial membrane potential (ΔΨm, JC1 assay) or reactive oxygen species (ROS, H2DCFDA assay). Expression levels of genes related to the following pathways were analyzed with qRT-PCR: Apoptosis (BAX, BCL2L13, CASP-3, -7, -9); angiogenesis (VEGFA, HIF1α, PDGF); integrins (ITGB-1, -3, -5, ITGA-3, -5, -V); mitochondrial biogenesis (PGC1α, POLG); oxidative stress (SOD2, GPX3, NOX4); inflammation (IL-6, -18, -1β, IFN-β1); and signaling (P3KCA, PI3KR1). Statistical analyses were performed using GraphPad Prism software. Results: The untreated AMD cybrids had significantly higher levels of cleaved caspase 3/7 compared to the untreated normal cybrids. The Bmab-treated AMD cybrids showed elevated levels of cleaved caspase 3/7 compared to untreated AMD or RSG-treated AMD cybrids. The Bmab-treated cybrids had lower ΔΨm compared to untreated AMD or RSG-treated AMD cybrids. The ROS levels were not changed with Bmab or RSG treatment. Results showed that Bmab-treated cybrids had higher expression levels of inflammatory (IL-6, IL1-β), oxidative stress (NOX4) and angiogenesis (VEGFA) genes compared to untreated AMD, while RSG-treated cybrids had lower expression levels of apoptosis (BAX), angiogenesis (VEGFA) and integrin (ITGB1) genes. Conclusions: These data suggest that the mechanism(s) of action of RSG, an integrin regulator, and Bmab, a recombinant monoclonal antibody, affect the AMD RPE cybrid cells differently, with the former having more anti-apoptosis properties, which may be desirable in treating degenerative ocular diseases.
Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial
Ophthalmic Surg Lasers Imaging Retina 2021 Jun;52(6):327-335.PMID:34185587DOI:10.3928/23258160-20210528-05.
Background and objective: To evaluate the safety and efficacy of 1.0 mg Risuteganib in subjects with nonexudative age-related macular degeneration (AMD). Patients and methods: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg Risuteganib or sham injection. At Week 16, subjects in the Risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg Risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the Risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. Results: Forty-five subjects (Risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (Risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and Risuteganib groups, respectively. The primary endpoint was met by 48% of the Risuteganib group at Week 28 and 7% of the sham group at Week 12 (P = .013). Of the Risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. Conclusions: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:327-335.].
Color Vision and Microperimetry Changes in Nonexudative Age-Related Macular Degeneration After Risuteganib Treatment: Exploratory Endpoints in a Multicenter Phase 2a Double-Masked, Randomized, Sham-Controlled, Crossover Clinical Trial
Ophthalmic Surg Lasers Imaging Retina 2022 Aug;53(8):430-438.PMID:35951718DOI:10.3928/23258160-20220725-02.
Background and objective: To explore the association between best-corrected visual acuity (BCVA) improvement and changes in microperimetry (MP) and color vision in patients with nonexudative age-related macular degeneration following administration of two 1.0-mg intravitreal doses of Risuteganib. Patients and methods: In a phase 2a, prospective, double-masked, sham-controlled study, eyes with nonexudative age-related macular degeneration and Early Treatment Diabetic Retinopathy Study BCVA between 20/40 and 20/200 were randomized to intravitreal Risuteganib (1.0 mg) or sham injection. The Risuteganib group received a second 1.0-mg dose, and patients in the sham group crossed over to receive 1.0 mg of Risuteganib at week 16. Exploratory endpoints included changes in color vision and mesopic MP. Results: Thirty-nine patients (Risuteganib, n = 25; sham, n = 14) completed the study. There was a significant (P < .05) correlation between BCVA and the total error score (TES) for both Lanthony and Hue Style. Confusion index was close to the criterion for significance (P = .056) in the Risuteganib group. All color vision metrics demonstrated a trend toward improvement in Risuteganib responders (BCVA letter gain ≥8 letters) and no change in the nonresponders, with significant differences seen in confusion index between the Risuteganib and control group (P = .0493) and between responders and nonresponders (P = .0478). MP showed that Risuteganib responders improved in mean sensitivity and change in number of loci ≤11 dB and ≤0 dB, whereas nonresponders worsened. Conclusion: All color vision and MP parameters tested trended toward improvement in risuteganib-treated patients and Risuteganib responders. Statistically significant improvement was evident in two metrics: confusion index (in risuteganib-treated patients and responders) and number of loci with decreased sensitivity (in responders). A significant correlation between BCVA and both TES Lanthony and TES Hue Style in Risuteganib patients provides concurrent evidence of objective and subjective improvement of retinal function. [Ophthalmic Surg Lasers Imaging Retina 2022;53:430-438.].