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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Kunitz domain is found in numerous proteases, including bovine pancreatic trypsin inhibitor (BPTI), human pancreatic secretory trypsin inhibitor (PSTI), and ecotin (periplasmic E. coli protease inhibitor). Kunitz domains are also involved as ion channel blockers as they mainly inhibit serine proteases. Structurally, kunitz domains are 60 amino acids long that are arranged in form of a mixture of α-helices and β-sheets. The core structure of the Kunitz domain is stabilized by three disulfide bonds that also make the structure compact and protect it from proteases (Ranasinghe and McManus, 2013). Lehmann et al. engineered small protein known as Ecallantide (DX-88) based on Kunitz domain using phage display technology. It acts as an inhibitor of plasma kallikrein that plays a major role in contact cascade to produce bradykinin (Lehmann, 2008). Dennis et al. designed Kunitz domain variants from Alzheimer’s amyloid beta-protein precursor inhibitor (APPI), to inhibit the association of human tissue factor-Factor VIIa complex (TF.FVIIa) (Dennis and Lazarus, 1994).
Preparation and characterization of angiopep-2 functionalized Ginsenoside-Rg3 loaded nanoparticles and the effect on C6 Glioma cells
Published in Pharmaceutical Development and Technology, 2020
Xiaomei Su, Danshen Zhang, Haiwei Zhang, Kaiyan Zhao, Wenshu Hou
Angiopep-2, a Kunitz domain-derived peptide from protease enzyme, is widely used as specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1). Actually, LRP-1 was found not only to be over-expressed on blood-brain barrier, but also expressed in malignant astrocytomas, especially in glioblastoma or glioma cells (Xin et al. 2012). Hence, LRP-1 would become a crucial target for the brain-targeting approach. Recent studies reported that LRP-1 successfully mediated the uptake of Angiopep-2, resulting in Angiopep-2 cross the blood-brain barrier and accumulated in parenchyma (Demeule et al. 2008).
Current and Future Options of Haemophilia A Treatments
Published in Expert Opinion on Biological Therapy, 2021
Wolfgang Miesbach, Fagr Eladly
A natural anticoagulant in the coagulation system is the Tissue Factor Pathway Inhibitor (TFPI), which inhibits the activation of extrinsic coagulation by interacting with the Factor VII/tissue factor complex and Factor X. Different molecules have been developed to inhibit TFPI. The most advanced is the development of humanized monoclonal antibodies such as Concizumab, which has already been successfully used in a Phase 1 study [47]. Concizumab is a monoclonal, humanized antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI.
The availability of new drugs for hemophilia treatment
Published in Expert Review of Clinical Pharmacology, 2020
Massimo Morfini, Emanuela Marchesini
Concizumab is a monoclonal, humanized IgG4 antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit hemophilia model. Restoration of thrombin generation is increasingly considered as a therapeutic intervention to overcome the limitations of protein replacement therapy. Anti-TFPI monoclonal antibodies restore thrombin generation by abolishing the inhibitory effect of TFPI on the initiation of coagulation.