Nomenclature of the Proteins of Cows’ Milk—Sixth Revision

Interaction of bovine (BSA) and human (HSA) serum albumins with ionic surfactants: spectroscopy and modelling.

Spectroscopic studies on the interaction of bovine (BSA) and human (HSA) serum albumins with ionic surfactants

Publisher Summary The role of plasma protein binding is recognized as an important factor in drug disposition and efficacy. This chapter discusses the structures of drug-binding proteins, particularly human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG), the relationship between ligand structure and protein binding and the effect of plasma protein binding on drug disposition and pharmacological activity. Human serum albumin (HSA) binds a wide variety of endogenous and exogenous ligands with association constants typically in the range of 10 4 to 10 6 M –1 . As the most abundant protein in plasma, it plays an important role in the maintenance of blood pH and colloidal osmotic pressure and accounts for most of the thiol content of plasma. Numerous competition and spectroscopic studies, using various ligands, have identified two sites (I and II) most relevant for drug binding. The interaction of various nonsteroidal anti-inflammatory drugs (NSAIDs) with HSA has been studied extensively. The interaction of other drug classes with HSA has also been investigated. Covalent modification of plasma proteins can be produced by direct attachment of an electrophilic moiety of the parent molecule to nucleophilic protein residues or by metabolic activation of the parent to a more reactive species. These reactions are important as their potential to form immunogenic adducts, with the possibility of producing idiosyncratic hypersensitivity reactions. Microdialysis is a potent technique to measure the extent of binding in vivo or in vitro in plasma. high-performance liquid chromatography (HPLC) methods, utilizing protein stationary phases, offer the potential for rapid screening, especially for those molecules bound to albumin. The blood brain barrier (BBB) effectively restricts the access of polar, hydrophilic drugs into the central nervous system (CNS), thus establishing a significant drug delivery impediment.

Chapter 33. Plasma Protein Binding of Drugs

Aggregation of amyloid-β peptides (Aβ) into fibrils is the key pathological feature of many neurodegenerative disorders. Typical drugs inhibit Aβ fibrillation by binding to monomers in 1:1 ratio and display low efficacy. Here, we report that model CdTe nanoparticles (NPs) can efficiently prevent fibrillation of Aβ associating with 100–330 monomers at once. The inhibition is based on the binding multiple Aβ oligomers rather than individual monomers. The oligomer route of inhibition is associated with strong van der Waals interactions characteristic for NPs and presents substantial advantages in the mitigation of toxicity of the misfolded peptides. Molar efficiency and the inhibition mechanism revealed by NPs are analogous to those found for proteins responsible for prevention of amyloid fibrillation in human body. Besides providing a stimulus for finding biocompatible NPs with similar capabilities, these data suggest that inorganic NPs can mimic some sophisticated biological functionalities of proteins.

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Inhibition of amyloid peptide fibrillation by inorganic nanoparticles: functional similarities with proteins.

Small-angle X-ray scattering (SAXS) was used to study structural characteristics of human serum albumin (HSA) in solution under different pH conditions. Guinier analysis of SAXS results yielded values of the molecular radius of gyration ranging from 26.7 A to 34.5 A for pH varying from 2.5 to 7.0. This suggests the existence of significant differences in the overall shape of the molecule at different pH. Molecular models based on subdomains with different spatial configurations were proposed. The distance distribution functions associated with these models were calculated and compared with those determined from the experimental SAXS intensity functions. The conclusion of this SAXS study is that the arrangement of molecular subdomains is clearly pH dependent; the molecule adopting more or less compact configuration for different pH conditions. The conclusions of this systematic study on the modification in molecular shape of HSA as a response to pH changes is consistent with those of previous investigations performed for particular pH conditions.

J. R. Olivieri

Papers

The subdomain structure of human serum albumin in solution under different pH conditions studied by small angle X-ray scattering