From Discovery of Snake Venom Disintegrins to A Safer Therapeutic Antithrombotic Agent

Kuo, Yu-Ju; Chung, Ching‐Hu; Huang, Tur‐Fu

doi:10.3390/toxins11070372

Cited by 24 publications

(15 citation statements)

References 73 publications

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“…Recently, new evidence has emerged on potentially important differences between thrombosis and hemostasis [ 24 , 25 , 26 ], thus raising the possibility of developing new antithrombotic drugs without increasing bleeding risk. Two potential strategies have been reported to achieve this end: (1) targeting factors that mediate the thrombus formation but do not affect the initial formation of the thrombus core [ 27 ] and (2) discovering inhibitors that bind to the extracellular domain of the integrin without causing receptor activation and conformational changes [ 28 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

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Improved Antithrombotic Activity and Diminished Bleeding Side Effect of a PEGylated αIIbβ3 Antagonist, Disintegrin

Kuo

Chang

Chung

et al. 2020

Toxins

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Polymer polyethylene glycol (PEG), or PEGylation of polypeptides improves protein drug stability by decrease degradation and reduces renal clearance. To produce a pharmaceutical disintegrin derivative, the N-terminal PEGylation technique was used to modify the disintegrin derivative [KGDRR]trimucrin for favorable safety and pharmacokinetic profiles and antithrombotic efficacy. We compared intact [KGDRR]trimucrin (RR) and PEGylated KGDRR (PEG-RR) by in vitro and in vivo systems for their antithrombotic activities. The activity of platelet aggregation inhibition and the bleeding tendency side effect were also investigated. PEG-RR exhibited optimal potency in inhibiting platelet aggregation of human/mouse platelet-rich plasma activated by collagen or ADP with a lower IC50 than the intact derivative RR. In the illumination-induced mesenteric venous thrombosis model, RR and PEG-RR efficaciously prevented occlusive thrombosis in a dose-dependent manner. In rotational thromboelastometry assay, there was no effect of PEG-RR in human whole blood coagulation even given at a higher concentration (30 μg/mL), while RR slightly prolonged clotting time. However, RR and PEG-RR were not associated with severe thrombocytopenia or bleeding in FcγRIIa-transgenic mice at equally efficacious antithrombotic dosages. We also found the in vivo half-life of PEGylation was longer than RR (RR: 15.65 h vs. PEG-RR: 20.45 h). In conclusion, injectable PEG-RR with prolonged half-life and decreased bleeding risk is a safer anti-thrombotic agent for long-acting treatment of thrombus diseases.

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Section: Discussionmentioning

confidence: 99%

“…For the synthesis of the PEG-RR ( Figure 1 ), the PEGylation was prepared as previously reported [ 24 , 25 ]. Firstly, RR mutant expressed in P. pastoris were purified to homogeneity by CaptoMMC chromatography and C 18 reversed-phase HPLC.…”

Section: Methodsmentioning

confidence: 99%

Improved Antithrombotic Activity and Diminished Bleeding Side Effect of a PEGylated αIIbβ3 Antagonist, Disintegrin

Kuo

Chang

Chung

et al. 2020

Toxins

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“…Some venom components inhibit platelet function, while other components induce platelet aggregation. Among platelet aggregation inhibitors, disintegrins have been recognized as unique and potentially valuable tools for examining cell-matrix and cell-cell interactions and for the development of antithrombotic and antiangiogenic agents [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Biomedical applications of snake venom: from basic science to autoimmunity and rheumatology

Cañas

Castaño-Valencia

Castro-Herrera

et al. 2021

Journal of Translational Autoimmunity

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Snake venoms have components with diverse biological actions that are extensively studied to identify elements that may be useful in biomedical sciences. In the field of autoimmunity and rheumatology, various findings useful for the study of diseases and potential drug development have been reported. The study of disintegrins, proteins that block the action of integrins, has been useful for the development of antiplatelet agents and principles for the development of immunosuppressants and antineoplastics. Several proteins in snake venoms act on the coagulation cascade, activating factors that have allowed the development of tests for the study of coagulation, including Russell’s viper venom time, which is useful in the diagnosis of antiphospholipid syndrome. Neurotoxins with either pre- or postsynaptic effects have been used to study neurogenic synapses and neuromuscular plaques and the development of analgesics, muscle relaxants and drugs for neurodegenerative diseases. Various components act by inhibiting cells and proteins of the immune system, which will allow the development of anti-inflammatory and immunosuppressive drugs. This review summarizes the usefulness of the components of snake venoms in the fields of autoimmunity and rheumatology, which can serve as a basis for diverse translational research.

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“…Such a pharmacological agent is 11-amino acid peptide pHB-SP (PubChem CID: 91810664), which is an amino acid chain QEQLERALNSS (Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser), having a selective affinity for the heterodimer complex EPOR/CD131 (Hache et al 2016). The short peptide chain allows its modification by adding the polypeptide motifs RGD (Arg-Gly-Asp), KGD (Lys-Gly-Asp) and PGP (Pro-Gly-Pro), which are known for their anti-aggregation properties (Pastorova et al 2001;Lyapina et al 2007;Liapina et al 2010;Obergan et al 2019;Kuo et al 2019). The key issue remains the retention of protective properties of innovative peptides mimicking the tertiary structure of the α-helix B of erythropoietin after embedding RGD, KGD and PGP motifs into the base molecule.…”

Section: Introductionmentioning

confidence: 99%

Preclinical study of innovative peptides mimicking the tertiary structure of the α-helix B of erythropoietin

Golubev¹,

Гуреев²,

Корокин³

et al. 2020

RRP

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Introduction: The aim of this study was to examine the effectiveness of innovative peptides obtained by addition of polypeptide motifs with antiaggregation activity (Arg-Gly-Asp, Lys-Gly-Asp and Pro-Gly-Pro) to a peptide mimicking the space structure of the α-helix B of erythropoietin pHBSP (Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser). Materials and methods: The cytoprotective activity of innovative peptides mimicking the space structure of the α-helix B of erythropoietin at the doses of 5 μg/ml, 30 μg/ml and 50 μg/ml was studied on human endothelial cell culture in a simulated oxidative stress. An ADMA-like model of preeclampsia was simulated in the experiment. The study was conducted in 260 female Wistar rats, weighing 250–300 g. Results and discussion: Innovative peptides mimicking the space structure of the α-helix B of erythropoietin retain their cytoprotective activity in a simulated oxidative stress in HUVEC cell culture at the doses of 5 μg/ml, 30 μg/ml, and 50 μg/ml. The compounds with laboratory codes P-αB1 and P-αB3 had the most pronounced cytoprotective activity. Administration of N-nitro-L-arginine-methyl ether to pregnant females for 7 days causes the morphofunctional changes similar to clinical changes in preeclampsia. The innovative peptide under laboratory code P-αB4 at the dose of 50 μg/kg mimicking the space structure of the α-helix B of erythropoietin shows the most pronounced protective properties. Conclusion: Innovative peptides mimicking the space structure of the α-helix B of erythropoietin have a pronounced positive influence on the morphofunctional disorders in animals with ADMA-like preeclampsia.

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From Discovery of Snake Venom Disintegrins to A Safer Therapeutic Antithrombotic Agent

Cited by 24 publications

References 73 publications

Improved Antithrombotic Activity and Diminished Bleeding Side Effect of a PEGylated αIIbβ3 Antagonist, Disintegrin

Improved Antithrombotic Activity and Diminished Bleeding Side Effect of a PEGylated αIIbβ3 Antagonist, Disintegrin

Biomedical applications of snake venom: from basic science to autoimmunity and rheumatology

Preclinical study of innovative peptides mimicking the tertiary structure of the α-helix B of erythropoietin

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