Search

The design of potent and pharmacologically effective, substrate-related inhibitors of renin has been the subject of intensive pharmaceutical discovery research for about one decade. Milestone achievements in synthetic tailoring of fragment analogs of angiotensinogen (ANG; Figure 1) have been documented in terms of identifying renin inhibitors of subnanomolar potency, sustained in vivo hypotensive activity, stability towards proteolytic degradation, and, more recently, oral bioavailability and decreased systemic clearance.1 By chemical modification of ANG-based derivatives, structure-activity analysis, and computer-assisted molecular modeling of peptidyl, pseudopeptidyl and peptidemimetic inhibitors using 3-D structural models of human renin, there currently exists a rather sophisticated wealth of information of relevance to the “rational” design of prototypic renin-targeted cardiovascular therapeutic agents. Such efforts have bridged biochemistry, medicinal chemistry, computational and biophysical chemistry, and in vivo pharmacology including, in a few cases, clinical evaluation in humans.

The dedication of yet another volume to the subject of the phospholipases A2 (PLA2) attests to the continued high level of interest in these enzymes. As will be evident from the articles contained herein, a major focus of interest is in regard to the involvement of PLA2 in the initiation of a metabolic cascade leading to the production of potent mediators of inflammatory diseases. Accordingly, an active search is underway for modulators or inhibitors of enzyme activity that might be useful in the treatment of inflammation, asthma, etc.. Furthermore, from a purely mechanistic point of view, the PLA2 have always been prime subjects for the study of interfacial catalysis. These enzymes are small, water soluble, stable, and work alone with only a requirement for calcium in their hydrolysis of water-insoluble phospholipids. Also, in contrast to the substrates of other lipolytic enzymes, phospholipids lend themselves ideally to such studies in that they form a variety of stable and structurally well-defined surfaces in micelles, reverse micelles, monolayers, planar bilayers, and curved vesicles with which to study catalysis at the boundary between two phases.

Enzymatic catalysis has fascinated biochemists and physical and organic chemists alike for several generations. By their specificity and their catalytic efficiency enzymes are even today the paragons of homogeneous catalysis, especially when catalysis in aqueous media at neutral pH values is concerned. Thus, the mechanism of enzymatic catalysis is the subject of more intense study than ever before.

Before discussing the structure of lipoproteins, a brief survey of the surface properties of their major constituents is in order. This will be followed by a discussion of the basic thermodynamic laws governing small spherical particles. The main discussion will be concerned with the gross structural features of lipoproteins, which can be predicted from the regularities observed in chemical composition as a function of particle size.