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Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01625 Daniel P. Teufel 1 , Gavin Bennett 1 , Helen Harrison 1 , Katerine van Rietschoten 1 , Silvia Pavan 1 , Catherine Stace 1 , François Le Floch 2 , Tine Van Bergen 2 , Elke Vermassen 2 , Philippe Barbeaux 2 , Tjing-Tjing Hu 2 , Jean H. M. Feyen 2 , Marc Vanhove 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01625 Daniel P. Teufel 1 , Gavin Bennett 1 , Helen Harrison 1 , Katerine van Rietschoten 1 , Silvia Pavan 1 , Catherine Stace 1 , François Le Floch 2 , Tine Van Bergen 2 , Elke Vermassen 2 , Philippe Barbeaux 2 , Tjing-Tjing Hu 2 , Jean H. M. Feyen 2 , Marc Vanhove 2
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Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biological matrices was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.
中文翻译：
稳定和持久的新型双环肽血浆激肽释放酶抑制剂治疗糖尿病性黄斑水肿
激肽释放酶激肽系统的成员激肽释放酶催化生物活性肽缓激肽的释放，从而引起炎症，血管舒张，血管通透性和疼痛。临床前证据暗示血浆激肽释放酶在糖尿病性视网膜病中的活性，这是患有糖尿病的患者视力丧失的主要原因。我们采用基于噬菌体展示技术并结合化学环化的技术，确定了对血浆激肽释放酶具有纳米和皮摩尔效价的高选择性双环肽抑制剂。在生物基质中的稳定性对于肽是固有的，或者是通过引入非天然氨基酸和非肽键进行工程改造的。该肽阻止缓激肽在体内和体外释放。在大鼠爪水肿模型和糖尿病诱导的视网膜通透性的啮齿动物模型中均证明了该药的有效性。玻璃体内给药后，双环肽在兔眼中具有约40小时的高度延长的半衰期，是治疗糖尿病性视网膜病变和糖尿病性黄斑水肿的有希望的新型药物。
更新日期：2018-03-08
中文翻译：
稳定和持久的新型双环肽血浆激肽释放酶抑制剂治疗糖尿病性黄斑水肿
激肽释放酶激肽系统的成员激肽释放酶催化生物活性肽缓激肽的释放，从而引起炎症，血管舒张，血管通透性和疼痛。临床前证据暗示血浆激肽释放酶在糖尿病性视网膜病中的活性，这是患有糖尿病的患者视力丧失的主要原因。我们采用基于噬菌体展示技术并结合化学环化的技术，确定了对血浆激肽释放酶具有纳米和皮摩尔效价的高选择性双环肽抑制剂。在生物基质中的稳定性对于肽是固有的，或者是通过引入非天然氨基酸和非肽键进行工程改造的。该肽阻止缓激肽在体内和体外释放。在大鼠爪水肿模型和糖尿病诱导的视网膜通透性的啮齿动物模型中均证明了该药的有效性。玻璃体内给药后，双环肽在兔眼中具有约40小时的高度延长的半衰期，是治疗糖尿病性视网膜病变和糖尿病性黄斑水肿的有希望的新型药物。
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