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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The number of possible three-dimensional shapes of a macromolecule is restricted by the nature of atoms behaving as hard spheres, with a definite radius meaning no two atoms can overlap, which restricts the number of possible bond angles in a polypeptide chain. This in turn, and in addition to steric factors where atoms hinder one another in a congested region of a molecule, puts constraints on the number of three-dimensional arrangements, or conformations, that the molecule can exhibit. In the case of proteins, steric hindrance from amino acid side chains and the way in which the electrons of the covalent bonds resonate between the amino acids, produce a rigid primary structure, where the amino acid side chains are held pointing outward in particular positions depending on the sequence of amino acids. This feature means that the polymer chain will fold into a predetermined secondary, and ultimately, tertiary structure. Here, nature works to ensure a specific molecule is made, needed for a specific function. If the primary structure had the full flexibility expected for single covalent bonds, the synthesis of proteins would be much more erroneous.
Antibodies to Lipids and Lipid Membranes: Reactions with Phosphatidylcholine, Cholesterol, Liposomes and Bromelin-Treated Erythrocytes
Published in E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson, Phospholipid-Binding Antibodies, 2020
The above paper noted a curious phenomenon.1 One of the lecithin formulations (obtained from Merck) apparently was contaminated with cholesterol and it induced the formation of antibodies both to lecithin and cholesterol. However, the antibodies produced in other animals to purified cholesterol did not react at all when assayed with the contaminated Merck lecithin. Moreover, when purified lecithin (from Boehringer) and cholesterol were directly mixed, the antibodies to cholesterol could not detect the cholesterol in the mixture. The authors concluded that “...the complement-binding function of cholesterol is considerably weakened or eliminated as a result of the addition of lecithin.” In modern terms this phenomenon is easily explained by the likelihood that addition of lecithin resulted in the formation of lecithin-cholesterol liposomal membranes, and binding of antibodies to cholesterol was blocked because of steric hindrance by the phosphocholine headgroups on the lecithin. The same phenomenon is observed today even with monoclonal antibodies to cholesterol.13 Steric hindrance phenomena play major roles in determining specificities of antibodies to lipids, and these issues will be discussed in further detail below.
Closed-Loop Plasmapheresis
Published in James L. MacPherson, Duke O. Kasprisin, Therapeutic Hemapheresis, 2019
Michael J. Lysaght, Walter Samtleben, Baerbel Schmidt, Hans J. Gurland
Hydroxyl matrices may be coupled with cyanogen bromide or chloro-S-triazine primary amines with glutaraldehyde and NaBH4. More sophisticated reaction routes are sometimes required to avoid steric hindrance or to promote binding at one side rather than another; attachment of the ligand at more than one site is also possible. The immunosorbents vary widely. Protein A is perhaps the most popular. This compound, which is usually isolated from Staphyloccocus aureus Cowan I, has a broad affinity for 3 of the 4 immunoglobulins (IgG1 IgG2, and IgG4) of the IgG class. Conveniently, it is commercially available both free and bound to sepharose (Pharmacia).* Heparin, which binds LDL, is frequently studied. A number of investigators have found naturally occurring materials (insulin, Factor IX, blood group antigen A/B) to matrices and then proceeded to remove pathogenic circulating antibodies to these natural materials. Thus far very few investigators have gone the more difficult — but more widely clinically relevant — route of preparing “synthetic” antibodies again specific circulating immunopathogens.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Mass spectrometry has several advantages compared to other RNA-small molecule ligand detection systems. First and foremost, both the RNA and the small molecules remain label-free. Various other systems such as small molecule arrays or fluorescently labeled systems often require modification of either the RNA or the small molecule ligands. These additional steps are time-consuming and can result in steric hindrance. Second, RNA-ligand binding affinity can be determined directly using mass spectrometry by varying the concentration of the ligand in relation to the RNA target [76], results from which compare well with other known means of measuring RNA-ligand binding affinity. Lastly, by modulating the RNA residues or fragmentation of the RNA-ligand complex and then measuring the fragmented ion abundance, the binding site of the small molecule on the RNA can be determined [76]. Combining all three methods, that is, label-free binding, binding affinity, and binding site, makes mass spectrometry a complete and powerful tool in determining RNA–small molecule ligand interactions. However, the technique is not without its limitations and complications. Probably the largest barrier to entry for this method is the cost of equipment and the expertise needed in accurately and efficiently running the experiment. Additionally, methods such as AS-MS are more suitable for single RNA target experimentation rather than multiplexing RNA targets. However, with sufficient mass differences between RNA targets, AS-MS may be adapted to multiplexing with several RNA targets.
Ulva lactuca methanolic extract improves oxidative stress-related male infertility induced in experimental animals
Published in Archives of Physiology and Biochemistry, 2021
Doaa A. Ghareeb, Alshimaa Abd-Elgwad, Nihal El-Guindy, Galila Yacout, Hala H. Zaatout
High gossypol consumption has biological toxicity because it can bind macromolecules before and after absorption. On one hand, it can interact with the substrate and thereby blocking the action of the digestive enzymes such as pepsin. On the other hand, it directly binds with the enzyme and changing the ionic character of the active site or creating steric hindrance (Wong et al.1972). Gossypol and its metabolites exert pro- and anti-oxidant potential. It was reported that gossypol increased the formation of ROS and DNA scission (Kovacic 2003). Bender et al. (1988) found that vitamin E, ascorbate, glutathione (GSH) peroxidase, and other antioxidants were reduced by feeding rats high levels of gossypol. Gossypol leads to male reproductive system toxicity and assists in maintaining long-term infertility through decreasing sperm motility and count, inhibits spermatogenesis, affects acrosomal formation, and spermatozoal elongation processes and causes Sertoli cells toxicity (Randel et al.1992, Wang 2000).
Enhanced detection of ATTR amyloid using a nanofibril-based assay
Published in Amyloid, 2021
M. Mahafuzur Rahman, Benjamin Schmuck, Henrik Hansson, Torleif Härd, Gunilla T. Westermark, Mats Sandgren
Steric hindrance prevents the antibody from simultaneous binding to all epitopes on a polyvalent antigen, where binding epitopes are closely spaced on the surface [31]. Thus, the addition of excess antibody in an immunolabeling experiment does not improve the reactivity. For immunolabeling experiments, lower antibody concentration is often preferred. However, lower antibody concentration may generate very weak signals, especially when targeting small antigen deposits (aggregates). Therefore, linking an additional antibody to the antigen, by any means, could offer a valuable tool in immunolabeling experiments. With the use of Ab-bNF, we succeeded in introducing 10-times more primary antibody to amyloid deposits on tissue sections, which resulted in very strong signals, indicating that our concept nicely tackles the steric hindrance issue. Moreover, our enhanced method demonstrated the potential to amplify fluorescence signals from minute amyloid deposits in tissue.