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Protein aggregation is a major instability that can occur during all stages of protein drug production and development. Protein aggregates may compromise the safety and efficacy of the final protein formulation. In this paper, various new excipients [phenylbutylamino-, benzyl-, and cholesteryl-polyethylene glycols (PEGs)] and their use for the reduction of aggregation of salmon calcitonin (sCT) and hen egg-white lysozyme (HEWL) by noncovalent PEGylation are presented. The ability to suppress aggregation of sCT in various buffer systems at a 1:1 molar ratio was assessed by following changes in protein conformation and aggregation state over time. The results are compared with that of dansyl- and L-tryptophan (Trp)-PEGs described in earlier publications. Furthermore, the influence of the different PEG-based excipients on the aggregation of HEWL was measured. HEWL aggregation was completely suppressed in the presence of cholesteryl-PEGs (2 and 5 kDa), whereas deterioration was observed using benzyl-methoxy polyethylene glycols (mPEGs; 2 and 5 kDa). Phenylbutylamino- and Trp-mPEG (2 kDa), as well as dansyl-PEGs of different molecular weight prolonged the lag phase of aggregation and reduced the aggregation velocity of HEWL., (Copyright © 2012 Wiley Periodicals, Inc.)

Oxidative damage to proteins, implicated amongst other in the etiology and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), results in the loss of specific biological protein function. A simple, sensitive, and cost-effective fluorimetric test to assess the antioxidant capacity of new chemical entities to protect proteins from loss of activity caused by reactive oxygen species (ROS) was developed using alkaline phosphatase (ALP) as model protein. Protein oxidation was induced by 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH) and the decrease in catalytic activity of ALP to hydrolyze 4-methylumbelliferyl phosphate (4-MUP) to fluorescent 4-methylumbelliferone (4-MU) was monitored as a marker of protein degradation. According to their capacity to protect ALP from peroxyl radical-induced activity loss, ten reference antioxidants were divided into three classes, namely efficient (pIC(50) > 5 for quercetin, chlorogenic acid, caffeic acid, mangiferin, and resveratrol), intermediate (4 < pIC(50) < or = 5 for melatonin, trolox, and ascorbic acid), and poor antioxidants (pIC(50) < 4 for glutathione and D-mannitol). Multifunctional drugs, having the ability to interact with several disease-related targets are of interest in PD. Therefore, the capacity of three catechol-O-methyltransferase (COMT) inhibitors, entacapone, nitecapone, and tolcapone to protect ALP from oxidative damage was also investigated and found to be very similar to the most potent reference antioxidants., (Copyright 2007 Wiley-Liss, Inc.)

A cellular automata model of a solute diffusing in water has been created and studied for the influential attributes. The results with this model are in agreement with experimental results; that is, that lipophilic solutes diffuse faster than do polar solutes. The model reveals that a solution composed of a relatively lipophilic solute permits a greater extent of diffusion of another solute. This observation is in agreement with the model showing a diffusion preference of a solute between two solutions made up of differing polarities. The solute diffuses farther into the lipophilic solution. A temperature-lipophilicity phase diagram shows the influence of these two attributes on the rate of diffusion. A model of diffusion through solutions containing stationary ingredients reveals a faster rate when the ingredient is lipophilic. We are led to a conclusion that the relative lipophilicity of solutes or stationary ingredients in a solution has a direct influence on the rates of diffusion of other solutes in their midst.

Human skin permeation data taken from the literature were analyzed for quantitative relationships with physicochemical properties and structural descriptors. No correlations exist with molecular weights and solvent-accessible surface areas. In most cases, skin permeation was inversely correlated with the parameter delta log Poct-hep (i.e., log Poctanol minus log Pheptane), which is mainly a measure of the H-bond donor acidity of the solutes. Lipophilicity itself, as expressed by log Poctanol, also contributes positively to skin permeation in some cases. The results of this quantitative structure-permeability relationship study are interpreted in terms of a unified mechanistic model whereby drugs can permeate via an intercellular route (correlation with both delta log Poct-hep and log Poct) and/or a transcellular route (correlation with log Poct only).

Published partition coefficient values of 121 solutes in five solvent systems (1-octanol-water, n-heptane-water, chloroform-water, diethyl ether-water, and n-butyl acetate-water) were correlated with solute properties, namely intrinsic molecular volume (indicator of cavity formation) and the solvatochromic parameters pi* (dipolarity/polarizability), beta (H-bond acceptor basicity), and alpha (H-bond donor acidity). While the cavity term and the H-bond accepting capacity played a comparable role in all solvent systems, the H-bond donor acidity was significant only in the alkane-water and chloroform-water systems. Comparison of the regression coefficients of pi*, beta, and alpha demonstrated the important role that water content at saturation in the organic solvents plays in the partitioning of solutes. Analysis of the differences between 1-octanol-water and n-heptane-water partition coefficients (delta log Poct-hep) and between 1-octanol-water and chloroform-water partition coefficients (delta log Poct-chf) showed that these values mainly quantitate the capacity of solute to donate hydrogen bonds. In contrast, the differences between 1-octanol-water and diethyl ether-water or n-butylacetate-water partition coefficients, (delta log Poct-dee and delta log Poct-ba, respectively) contain no structural information.