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Osteoarthritis (OA) is a common group of disabling joint disorders for which there are limited pharmacological therapies to alter disease progression. Zoledronate, one of several bisphosphonates found to modulate joint changes in animal OA models, may have a disease-modifying role, and potential mechanisms of action include effects on cartilage and/or subchondral bone. In OA cartilage, loss of aggrecan, the main glycosaminoglycan-bearing proteoglycan, and degradation of type II collagen are major biochemical changes arising from imbalances in matrix synthesis and degradation. Zoledronate, in common with other bisphosphonates, is capable of inhibiting matrix metallo-proteinases, enzymes implicated in OA cartilage matrix catabolism, providing a biochemical basis for cartilage effects but it is not known whether direct effects occur at the cell/tissue level. Studies described in this thesis have explored the hypothesis that zoledronate modifies cartilage metabolism to reduce cartilage glycosaminoglycan loss in OA. Short-term treatment effects on proteoglycan synthesis and degradation were examined in vitro in models of cartilage and chondrocyte metabolism, with IL-1a used to stimulate "OA-like" tissue glycosaminoglycan release. Zoledronate 10M adversely affected cell viability, proliferation and proteoglycan synthesis in bovine articular chondrocytes and, thus, was the upper limit of the concentration range investigated. No enhancing effects were observed with zoledronate 10"10M to 10/1 on proteoglycan synthesis in bovine articular chondrocytes. No effects on glycosaminoglycan release were seen with zoledronate 10"10M to 10"5M in bovine articular cartilage or with zoledronate 10"8M to "10M in alginate bead constructs containing bovine articular chondrocytes and matrix. Thus, a direct effect on cartilage proteoglycan metabolism following short-term treatment does not appear to be a mechanism of action for zoledronate as a disease-modifying treatment in OA. However, preventative or delayed treatment effects remain unaddressed and other potential targets for zoledronate in the OA joint include cartilage type II collagen metabolism and subchondral bone metabolism.

The Flaviviridae is a family of 66 viruses of which almost half have been associated with human disease. The most well-known members are: Hepatitis C virus (HCV), Dengue virus (DV), and West Nile virus (WNV). Diseases caused by these viruses are a global health problem that put an estimated 2.5 billion people at risk. At present, there are neither vaccines nor other treatments available to prevent or cure these diseases. Potential targets for the development of therapeutics against the virus are the viral protease and polymerase. The aims of this project are to design and synthesize compounds that can be used as inhibitors for these two key enzymes for Dengue. Structure-based drug design methods utilize knowledge of a three dimensional structure of an enzyme/receptor to develop small molecules able to bind to the desired target, generating a specific biological response. These computer-based methodologies are now becoming an integral part of the drug discovery process and, although the principles of molecular recognition are far from being completely understood, some marketed compounds (i.e. Zanamivir, Lopinavir) have been developed with the help the of successful application of structure-based design techniques. Different structure-based drug design approaches have been used to identify putative new inhibitors for the Dengue protease and polymerase. A pharmacophore query has been built based on the active site of the Dengue protease enzyme and then used for screening different databases for identification of potential inhibitors. For the polymerase, a fragment-based approach has been used to find the fragments that would interact more efficiently with a specific binding pocket on the enzyme. The virtual library obtained by linking the best scored fragment was then docked to identify the most promising structures to be synthesized. The identification of potent small molecules that bind to receptors and enzymes is one of the major goals of chemical and biological research.