Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema

Teufel, Daniel P.; Bennett, Gavin; Harrison, Helen; Rietschoten, Katerine Van; Pavan, Silvia; Stace, Catherine; Floc'h, F. Le; Bergen, Tine Van; Vermassen, Elke; Barbeaux, Philippe; Hu, Tjing-Tjing; Feyen, Jean H.M.; Vanhove, Marc

doi:10.1021/acs.jmedchem.7b01625

Cited by 38 publications

(41 citation statements)

References 68 publications

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“…Deficient regulation of the system is exemplified by the disorder hereditary angioedema where reduction of the natural inhibitor serpin C1 or a hyperactivated FXII results in excessive bradykinin generation and recurrent attacks of severe tissue swelling . PKa is currently being targeted as a novel means to treat diverse thrombotic and inflammatory disorders such as diabetic macular edema , desquamating skin diseases, and neurodegenerative disorders .…”

Section: Introductionmentioning

confidence: 99%

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Voos

Pathak

et al. 2019

Journal of Thrombosis and Haemostasis

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Zymogen PK is activated to PKa and cleaves substrates kininogen and FXII contributing to bradykinin generation. Monomeric PKa and dimeric homologue FXI utilize the N‐terminal apple domains to recruit substrates. A high‐resolution 1.3 Å structure of full‐length PKa reveals an active conformation of the protease and apple domains. The PKa protease and four‐apple domain disc organization is 180° rotated compared to FXI. Summary BackgroundPlasma prekallikrein (PK) and factor XI (FXI) are apple domain‐containing serine proteases that when activated to PKa and FXIa cleave substrates kininogen, factor XII, and factor IX, respectively, directing plasma coagulation, bradykinin release, inflammation, and thrombosis pathways. ObjectiveTo investigate the three‐dimensional structure of full‐length PKa and perform a comparison with FXI. MethodsA series of recombinant full‐length PKa and FXI constructs and variants were developed and the crystal structures determined. Results and conclusionsA 1.3 Å structure of full‐length PKa reveals the protease domain positioned above a disc‐shaped assemblage of four apple domains in an active conformation. A comparison with the homologous FXI structure reveals the intramolecular disulfide and structural differences in the apple 4 domain that prevents dimer formation in PK as opposed to FXI. Two latchlike loops (LL1 and LL2) extend from the PKa protease domain to form interactions with the apple 1 and apple 3 domains, respectively. A major unexpected difference in the PKa structure compared to FXI is the 180° disc rotation of the apple domains relative to the protease domain. This results in a switched configuration of the latch loops such that LL2 interacts and buries portions of the apple 3 domain in the FXI zymogen whereas in PKa LL2 interacts with the apple 1 domain. Hydrogen‐deuterium exchange mass spectrometry on plasma purified human PK and PKa determined that regions of the apple 3 domain have increased surface exposure in PKa compared to the zymogen PK, suggesting conformational change upon activation.

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Section: Introductionmentioning

confidence: 99%

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Voos

Pathak

et al. 2019

Journal of Thrombosis and Haemostasis

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“…Preclinical safety of bicyclic peptide was assessed upon systemic administration in rats and cynomolgus non-human primates. No overt toxicological effect observed at the highest tested systemic dose of 125 μg (0.43 − 0.60 mg/kg) in rats and 1.25 mg (0.42 − 0.49 mg/kg) in cynomolgus non-human primates [56].…”

Section: Thr-149mentioning

confidence: 89%

“…THR-149 (Oxurion NV) is a potent human plasma kallikrein bicyclic peptide inhibitor developed using a phage display-based selections of constrained peptide libraries combined with rationally designed synthetic modifications. The pharmacodynamic effect of a bicyclic peptide was assessed in a streptozotocin (STZ) induced retinal permeability in a rodent model [56]. A significant reduction in retinal vascular leakage was observed at 4 weeks, compared to the vehicle-treated group, following an intravitreal administration of a bicyclic peptide inhibitor (100 μg/eye).…”

Section: Thr-149mentioning

confidence: 99%

Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment

Bhatwadekar

Kansara

Ciulla

2020

Expert Opinion on Investigational Drugs

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Introduction: Plasma kallikrein is a mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclinical models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patients to anti-VEGF agents, and the treatment burden associated with frequent dosing, there is still considerable need for VEGF-independent targeted pathways. Areas covered: This review covers the role of plasma kallikrein in the pathogenesis of DME and the therapeutic potential of plasma kallikrein inhibitors. It discusses early clinical studies of plasma kallikrein pathway modulation for DME, which have been associated with some improvement in visual acuity but with limited improvement in macular edema. This review also highlights KVD001, which is furthest along the development pathway, THR-149, which has recently completed a phase 1 study, and oral agents under development. Expert opinion: Plasma kallikrein inhibitors have a potential role in the treatment of DME, with mixed functional/anatomic results in early clinical trials. Given the large unmet need in DME treatment, further studies are warranted.

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“…The effects of both classes on diabetic retinopathy are also very different. Some studies have suggested that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats [13, 25] and that its inhibitors can improve diabetic macular oedema [26]. Other studies have shown that tissue kallikrein improves diabetic retinopathy by inhibiting retinal vascular permeability and VEGF increases in diabetic rats [14].…”

Section: Discussionmentioning

confidence: 99%

Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-Ay/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes

Cheng

Jie

et al. 2019

Diabetologia

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Aims/hypothesis Many studies have shown that tissue kallikrein has effects on diabetic vascular complications such as nephropathy, cardiomyopathy and neuropathy, but its effects on diabetic retinopathy are not fully understood. Here, we investigated the retinoprotective role of exogenous pancreatic kallikrein and studied potential mechanisms of action. Methods We used KK Cg- A y /J (KKAy) mice (a mouse model of spontaneous type 2 diabetes) and mice with high-fat diet/streptozotocin (STZ)-induced type 2 diabetes as our models. After the onset of diabetes, both types of mice were injected intraperitoneally with either pancreatic kallikrein (KKAy + pancreatic kallikrein and STZ + pancreatic kallikrein groups) or saline (KKAy + saline and STZ + saline groups) for 12 weeks. C57BL/6J mice were used as non-diabetic controls for both models. We analysed pathological changes in the retina; evaluated the effects of pancreatic kallikrein on retinal oxidative stress, inflammation and apoptosis; and measured the levels of bradykinin and B1 and B2 receptors in both models. Results In both models, pancreatic kallikrein improved pathological structural features of the retina, increasing the thickness of retinal layers, and attenuated retinal acellular capillary formation and vascular leakage ( p < 0.05). Furthermore, pancreatic kallikrein ameliorated retinal oxidative stress, inflammation and apoptosis in both models ( p < 0.05). We also found that the levels of bradykinin and B1 and B2 receptors were increased after pancreatic kallikrein in both models ( p < 0.05). Conclusions/interpretation Pancreatic kallikrein can protect against diabetic retinopathy by activating B1 and B2 receptors and inhibiting oxidative stress, inflammation and apoptosis. Thus, pancreatic kallikrein may represent a new therapeutic agent for diabetic retinopathy. Electronic supplementary material The online version of this article (10.1007/s00125-019-4838-9) contains peer reviewed but unedited supplementary material, which is available to authorised users.

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Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema

Cited by 38 publications

References 68 publications

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment

Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-Ay/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes

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