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Rapid Formation of Plasma Protein Corona Critically Affects Nanoparticle Pathophysiology
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Stefan Tenzer, Dominic Docter, Jörg Kuharev, Anna Musyanovych, Verena Fetz, Rouven Hecht, Florian Schlenk, Dagmar Fischer, Klytaimnistra Kiouptsi, Christoph Reinhardt, Katharina Landfester, Hansjörg Schild, Michael Maskos, Shirley K. Knauer, Roland H. Stauber
However, to facilitate their continuative rational identification, corona proteins were classified bioinformatically according to their physiological molecular functions (Fig. 9.4a). Not only nanoparticle characteristics, but also plasma exposure time clearly affected the abundance of factors associated with processes such as complement activation, cell death, immune response [36], coagulation and acute-phase response (Fig. 9.4b–g and Supplementary Figs. S13 and S14). Our quantitative analysis also allowed calculations of protein copy number/nanoparticle (Fig. 9.1e, Supplementary Fig. S15 and Tables S6 and S7), and thereby facilitated rational selection of candidate proteins for subsequent studies [1, 8, 11, 37]. Assuming a random distribution, low-abundance proteins (<1 molecule/nanoparticle) are less likely to trigger nanoparticle-induced biological responses. Most identified proteins were, however, present at >1 molecule/nanoparticle, which underlines their relevance. Supplementary Table S8 lists the most-abundant coagulation-relevant corona proteins for each nanoparticle that contain not only factors that promote, but also those that counteract coagulation cascades [17]. Whereas kininogen-1, which plays a central role for the function of the kallikrein–kinin–kininogen system [38], remains predominantly adsorbed on silica nanoparticles, on polystyrene particles it was replaced rapidly by prothrombin or integrin α-IIb.
Escherichia coli
Published in Yoshikatsu Murooka, Tadayuki Imanaka, Recombinant Microbes for Industrial and Agricultural Applications, 2020
Hisashi Yasueda, Hiroshi Matsui
Since, the isolated fusion proteins themselves are not normally suitable as end products (e.g., for clinical use), it is generally necessary to specifically cleave the fusion protein to release the desired native gene product. Cleavage usually involves specific chemical or endopeptidase treatment. For chemical treatment, cyanogen bromide [1,101,102], formic acid [96], and hydroxyl-amine [104,105] are employed in the cleavage reaction. For enzymes, blood coagulation factor Xa [98,100,106], human plasma kallikrein [107], collagenase [95,108], enterokinase [109], thrombin [98,103,110], and ubiquitin-protein hydrolase [111] have been used. Unfortunately, some fusion systems are both complicated and costly, particularly, when applied on a large scale, because of the need to use delicate and expensive enzymes to release the desired mature gene product.
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).
A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity
Published in Science and Technology of Advanced Materials, 2019
Kristina N Ekdahl, Karin Fromell, Camilla Mohlin, Yuji Teramura, Bo Nilsson
Like the complement system, the contact, kallikrein/bradykinin, and coagulation systems are under strict control in vivo. Antithrombin (AT) is the most important inhibitor that inactivates, in particular, FXa, FIXa, FVIIa, and thrombin. The effect of AT is increased dramatically in the presence of heparin or heparan sulfate (see below). FXIIa and FXIa are primarily inhibited by C1INH and to a lower degree of AT.