15-Lipoxygenase and Its Inhibition: A Novel Therapeutic Target for Vascular Disease. Pp. 11-20.
J. A. Cornicelli and B. K. Trivedi
[Abstract]
Parathyroid Hormone and Parathyroid Hormone-Related Protein: Model Systems for the Development of an Osteoporosis Therapy. Pp. 21-36.
Dale F. Mierke and Maria Pellegrini
[Abstract]
[Back to top] Therapeutic Strategies for Coronary Artery Disease Beyond Low Density Lipoprotein (LDL)--Lowering. Yadon Arad and Uday Saxena.
Coronary artery disease (CAD) ranks as the leading cause of death in the western world. The most widely used therapeutics utilized for the treatment of CAD are the lipid-lowering drugs, which lower plasma cholesterol. However lowering cholesterol alone may not he sufficient to provide benefit to all patient populations at risk for CAD. This creates an unmet medical need. Emerging knowledge of the genesis, progression and regression of atherosclerosis, that leads to CAD permits evaluation of other therapeutic strategies.
This review will evaluate two such naturally occurring paradigms, the nitric oxide pathway and the high-density lipoprotein system which are nature's defense mechanisms against atherosclerosis and may lead to next generation therapeutics against CAD.
[Back to top] 15-Lipoxygenase and Its Inhibition: A Novel Therapeutic Target for Vascular Disease. J. A. Cornicelli and B. K. Trivedi.
The disease process known as atherosclerosis is the leading cause of morbidity and mortality in the Western world. Current therapies have focused on treating the major risk factors identified to date including plasma lipid derangements, hypertension, clotting disorders, and diabetes. However, a significant number of individuals will be diagnosed with this malady in the apparent absence of known risk factors. Recent attention has turned toward treating the disease at the level of the vessel wall. In this review, we assess the relevancy of the oxygenating enzyme 15-lipoxygenase (15-LO) as a therapeutic target. In vitro studies suggest that this enzyme may be involved in processes that modify native LDL in such a way as to be avidly taken up by tissue macrophages. In support of this contention are reports demonstrating the colocalization of 15-LO with macrophage-rich arterial lesions and epitopes of modified LDL. Investigations using transgenic animals also suggest that the site of 15-LO expression may be an important factor in the development of the disease. The alteration of important cellular fatty acids may also generate intracellular signals that promote a pro-atherogenic phenotype in the absence of measurable changes in bulk lipid peroxidation. A limited number of studies have examined 15-LO inhibitors and those structural determinants necessary for inhibition of the enzyme. These include natural products and synthetic analogs. Structure activity relationships have been defined for a number of compounds including caffeic acid derivatives, propargyl ethers, and catechols. A novel, potent, specific inhibitor of 15-LO that lacks significant antioxidant activity was tested for its ability to inhibit atherosclerotic lesion formation in vivo. This benzothiopyranoindole virtually eliminated lesion formation in two animal models in the absence of significant changes in plasma lipids. Further, it prevented the progression of pre-established lesions in another study. Collectively, these data provide a strong scientific rationale for exploring the inhibition of 15-LO as a therapeutic strategy.
[Back to top] Parathyroid Hormone and Parathyroid Hormone-Related Protein: Model Systems for the Development of an Osteoporosis Therapy. Dale F. Mierke and Maria Pellegrini.
The parathyroid hormone (PTH) plays a vital role in the homeostasis of calcium within the blood stream. Given its unique ability to increase bone density, an understanding of the molecular mechanism by which the hormone is recognized and binds to its receptor should provide targets for the development of PTH--based, anabolic agents for the treatment of osteoporosis. Parathyroid hormone related protein ( PTHrP), a genetically and structurally distinct hormone which displays similar binding and activation profiles as PTH, has greatly facilitated the effort to establish a structure-biological function relationship by allowing for direct comparisons. In an analogous manner, the presence of two receptors, PTH/PTHrP (PTH1) and PTH2, which differ in their ligand selectivity (PTH2 is activated by PTH, not PTHrP) has provided a unique vehicle for probing the structural motifs of the receptor required for ligand recognition and binding. Recent photo-affinity cross-linking studies of PTH and PTHrP binding to PTH1 have produced direct points of contact between the ligand and receptor. Here, we review each of the components involved in this important hormone system, with particular emphasis on the structural features of each: the ligands (PTH and PTHrP), the receptors (PTH1 and PTH2), and the interaction between ligand and receptor. Although the current understanding of the molecular mechanism of ligand binding and receptor activation does not allow for the rational design of drug candidates, and indeed contains much conjecture, significant strides have been made towards this end.