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Organoids as an Emerging Tool for Nano-Pharmaceuticals
Published in Harishkumar Madhyastha, Durgesh Nandini Chauhan, Nanopharmaceuticals in Regenerative Medicine, 2022
At a cellular level, after sensing the cues, these cues may be processed as external stimuli by modulating the microenvironment and inducing specific responses through activation of genetic programme, known as the mechanotransduction process (Chan et al. 2017, Davidson 2017). These biophysical signals are interpreted by a set of specialised proteins and their dysregulation, in turn, leads to various pathologies. Vinculin is an important mechanotransducter, serving as a linker for integrins to cytoskeleton, and pathogenic variations in this protein in humans are reported in various pathologies like cancer, cardiomyopathies, and neural defects (Olson et al. 2002, Vasile et al. 2006, Liang et al. 2014, Chinthalapudi et al. 2016).
Pharmaceutical Industry
Published in Roger Cooter, John Pickstone, Medicine in the Twentieth Century, 2020
During the 1970s and early 1980s, however, and within the context of a significant and seemingly relentless fall in the number of new drugs placed on the market — the number of new single entity drugs introduced to the American market between 1970 and 1985 was 40% down on the previous fifteen years — pharmaceutical research began to look for new search techniques. Rather than focusing on the chemical, research turned to the target, particularly to receptor geometry and biophysics. With the insight of molecular biology and computer technology, model compounds could be designed to block the receptors and thereby stem the natural history of the specific condition. This rational approach, as it has been called, is also designed to take the chanciness out of drug discovery.
Features of Lipid Metabolism in Diabetes Mellitus and Ischemic Heart Disease
Published in E.I. Sokolov, Obesity and Diabetes Mellitus, 2020
All these problems are solved at the junction of several specialities: biochemistry, biophysics, morphology, and internal diseases. A number of scientists showed that in syndrome X there appear tissue hypoxia and ischemia of the myocardium cells pointing to the great significance of the membrane phospholipases in the irreversible lesion of cells. The lipid bilayer of membranes acquire electrical instability and lose their barrier functions. In recent years, major significance in the pathogenesis of atherosclerosis is attached to the peroxide oxidation of lipids. The use of antioxidants inhibiting the peroxide oxidation of lipids was found to affect deeply the lipid composition and physical properties of all membrane structures of the cells, and this may be the theoretical basis for the use of antioxidants as an important therapeutic factor in atherosclerosis.
Assessing developability early in the discovery process for novel biologics
Published in mAbs, 2023
Monica L. Fernández-Quintero, Anne Ljungars, Franz Waibl, Victor Greiff, Jan Terje Andersen, Torleif T. Gjølberg, Timothy P. Jenkins, Bjørn Gunnar Voldborg, Lise Marie Grav, Sandeep Kumar, Guy Georges, Hubert Kettenberger, Klaus R. Liedl, Peter M. Tessier, John McCafferty, Andreas H. Laustsen
To realize the full utility of the cellular assays described above, the biophysical properties of biologics need to be considered. Factors such as the surface charge of Fc-fused structures may affect the cellular handling of biologics in both FcRn-dependent and independent manners. For example, the antibodies briakinumab and ustekinumab bind to the same target, the p40 subunit of IL12/23, but their varying charge profiles confer vastly different half-lives in humans.169,183,192,193 Specifically, the charge of the briakinumab Fv alters its interaction with FcRn.169,183,194 Cellular studies have revealed that this causes FcRn-independent cellular accumulation of briakinumab, which explains its shorter half-life.183 Interestingly, the same study found that the half-life of briakinumab can be improved by Fc-engineering, exemplifying that modulating the core binding to FcRn may adjust for unfavorable biophysical traits of Fc-fused structures. It also exemplifies the complexity tailored cellular assays may reveal. These are just a few of many existing examples of how distal structural traits may affect Fc binding to FcRn.164,194,195 Furthermore, HERA and other cellular assays can also be used to address transport of albumin-based molecules, which reflect their in vivo pharmacokinetic properties and ability to cross polarized mucosal epithelial cell surfaces.165,167,184,196
Biochemical and biophysical properties of an unreported T96R mutation causing transthyretin cardiac amyloidosis
Published in Amyloid, 2023
Meng Jiang, Mengdie Wang, Zhengyu Tao, Yezi Chai, Qiming Liu, Qifan Lu, Qizhen Wu, Xiaoying Ying, Yanan Huang, Ying Nie, Yuqi Tang, Xin Zhang, Yu Liu, Jun Pu
In this study, we presented the unreported TTR mutation T96R occurring in China (c.347C > G p.T116R and referred to as T96R and owing to its cleavage of the first 20 amino acids targeting sequence during secretion). This mutation is located on the β-strand F of TTR. The patient is a 60-year-old male who primarily presented with recurrent palpitations and shortness of breath. After thorough cardiac imaging, endomyocardial biopsy and genetic study, a diagnosis of ATTR-CM was made. Biochemical and biophysical tests were conducted to measure the thermodynamic and kinetic stability of this novel mutation. A subsequent heterozygous exchange experiment used a crosslinking assay to explore the pathogenicity of this mutation. Additionally, we measured the binding constants of small molecule drugs and TTR T96R mutant proteins using both an amyloid formation inhibition assay and isothermal titration calorimetry (ITC). Collectively, our biochemical and biophysical results support the clinical observations.
Current advances in biopharmaceutical informatics: guidelines, impact and challenges in the computational developability assessment of antibody therapeutics
Published in mAbs, 2022
Rahul Khetan, Robin Curtis, Charlotte M. Deane, Johannes Thorling Hadsund, Uddipan Kar, Konrad Krawczyk, Daisuke Kuroda, Sarah A. Robinson, Pietro Sormanni, Kouhei Tsumoto, Jim Warwicker, Andrew C.R. Martin
There can be opportunities to address the underlying balance of biophysical forces that drive interactions when developing models to predict the properties of biopharmaceutical candidates. Two such examples are discussed here, one relating to the measurement of hydrophobic interactions and the other to the protein structural basis of hydrophobic interaction between proteins. Several machine learning methods to predict the HIC retention time from antibody sequence input have been reported previously in the literature.33,40,129 Assessment of aggregation propensity using HIC was the best-predicted biophysical property across 12 models produced using Abpred (www.protein-sol.manchester.ac.uk/abpred), one for each of the 12 biophysical properties measured across a set of antibodies.40 Even so, there was a marked reduction in performance of the model for antibodies with higher retention times in HIC, leading to a model in which the salt gradient that is used to modulate hydrophobic interaction strength also affects interactions between charged proteins. A revised scheme was derived in which charge interactions play a role alongside hydrophobic effects in the HIC method. In this scheme, proteins with higher net charge repel more within the column when salt concentration (ionic strength) is lower, and are eluted faster, than proteins with lower net charge but the same hydrophobicity.