Mini Reviews in Medicinal Chemistry - Volume 1, Issue 2, 2001

More than ten years have now elapsed since the first reports confirmed that antibodies not only label antigenic targets but can also perform catalytic functions. Much of the initial research in this area focussed on exploring the scope and utility of these biocatalysts both as enzyme mimics and as programmable protein catalysts. However, their potential in the biomedical field has also been probed. This review details the present perspective of catalytic antibodies as new tools for immunotherapy and specifically focuses on their application to prodrug activation and drug inactivation.

In this review we focus on the most effective and the most promising inhibitors of leucine aminopeptidase. Their binding modes to the enzyme, the attempt to explain the origin of the inhibitory activity, as well as the structure - activity relationship for some of these compounds are discussed. Besides, the structural and electronic requirements of the enzyme active site and the binding pockets, together with the specificity towards the ligands, based on the structural and kinetic data, are presented.

Sugar-mimicking alkaloids inhibit the glycosidases involved in a wide range of important biological processes, principally owing to their structural resemblance to the sugar moiety of the natural substrate. The possibility of modifying and blocking these processes by using such inhibitors for therapeutic applications has attracted a lot of attention.

The stereospecificity shown by a wide variety of inhibitors that are effective for carboxypeptidase A (CPA), a representative zinc protease is analyzed on the basis of inhibitor type. In cases of ground state analog inhibitors and transition state analog inhibitors, the stereoisomers having the stereochemistry that corresponds to stereochemistry of substrate are more potent, but in the case of irreversible inhibitors including mechanism-based inactivators the preferred inhibitory stereochemistry cannot be predicted simply from the substrate stereospecificity. The Ogston three point fit concept may be of great value in understanding the inhibitory stereochemistry of reversible competitive inhibitors. On the other hand, the stereochemistry of irreversible inhibitors may possibly be predicted on the ground of the transition state structure that plays a critical role in the inactivation pathway.

Tacrine-huperzine A hybrids (huprines) are a new class of very potent and selective acetylcholinesterase (AChE) inhibitors. Huprines were designed from tacrine and (-)-huperzine A through a conjunctive approach. They combine the 4-aminoquinoline substructure of tacrine with the carbobicyclic substructure of (-)-huperzine A. Structural variations on several parts of a lead structure have allowed to complete a structure-activity relationship exploration of this new structural family and have led to several huprines more active than other known AChE inhibitors.

Amyloid (A beta) deposition remains a hallmark in the pathology of Alzheimer disease (AD). Important drug discovery efforts dedicated to the inhibition of the polymerization process leading to amyloid neurotoxicity are pursued by academic groups and the pharmaceutical industry as a potential preventive treatment for AD. The aim of this review is to up-date current knowledge on the amyloid aggregation process and the various available peptidic and non-peptidic A beta aggregation inhibitors.

The analysis of structure-activity relationships started probably more than hundred years ago but the concept of quantitatively correlating physicochemical properties of molecules with their biological activities, termed as quantitative structure-activity relationship (QSAR), was initiated by Corwin Hansch and his groups in early 1960. Many new methods have emerged since then. The concept evolved from 2D QSAR to 3D QSAR and lately another dimension (4D QSAR) has been added. This evolution is briefly reviewed here.

The majority of newly-identified genes in the human genome show no significant sequence similarity to genes whose function is known, so they are not easily recognized as potential drug targets. Expression analysis is an alternative method to suggest possible functions of genes. We review statistical methods for gene expression analysis to identify potential pharmaceutical targets. Specifically, we illustrate the analysis of differential gene expression (using discriminant analysis, t-tests, and analysis of variance) and co-expression (using correlation, clustering, and chi-square). We present an example of the use of expression analysis to identify co-expressed cardiomyopathy-associated genes.

Angiotensin II, the primary active hormone in the Renin-Angiotensin System is a major vasoconstrictor implicated in the cause of hypertension. Research efforts have focused in the treatment of disease by blocking its release and more recently by competing its action on AT 1 receptors. This approach generated in the pharmaceutical market, losartan, and other derivatives. To better understand the stereoelectronic requirements that lead to the molecular basis of hypertension the stereochemical features of angiotensin II and its antagonists are studied.