Arthritis-associated proteins

Similar in approach to linear methods discussed previously, the cyclodehydration of a-amido ketones is an alternative strategy for preparation of the oxazole nucleus. Treatment of the ketone with PPhs and I2 results in cyclization to provide the fully substituted oxazole nucleus in excellent yield. This strategy was recently used in the synthesis of oxazole-modified glycopeptides, designed to target two classes of arthritis-associated proteins. The oxazole was probed as a conformationally locked dipeptide mimic. 

An interesting approach to the treatment of autoimmune diseases is design of peptide mimics that bind into the antigen-binding groove of specific MHC proteins. For example, a protease-resistant pyrrolinone-peptide hybrid has been designed to bind to the rheumatoid-arthritis-associated HLA-DR1.326... 

Williams RC Jr, Sugiura K, Tan EM (2004) Antibodies to microtubules associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 50 1239-1247. 

Yoshinouchi T, Ohtsuki Y, Ueda R, et al. Myofibroblasts and S-100 protein positive cells in idiopathic pulmonary fihrosis and rheumatoid arthritis-associated interstitial pneumonia. Eur Respir J 1999 14 579 584. 

In the past number of years a number of studies have shown that in a variety of diseases there is a significant oxidation of Met residues to Met(O) in specific proteins that results in a loss of biological activity. These diseases include cataracts, rheumatoid arthritis, adult respiratory distress syndrome and emphysema. The most convincing evidence that Met(O) in proteins may be involved in the etiology of a pathological condition comes from studies with a-l-PI. It is well accepted that a-l-PI is inactivated upon oxidation of its Met residues. A decreased activity of a-l-PI in lung tissue that would result in an increased elastase activity has been associated with pulmonary emphysema. In patients who have a... 

Matrix metalloproteinases (MMPs) are a class of zinc- and calcium-dependent enzymes that are responsible for the metabolism of extracellular matrix proteins [27]. Increased activity of MMPs has been associated with pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer s disease [28-31]. Therefore, they constitute an important group of drug targets. Their inhibition is accomplished by blocking the active site of the catalytic domain with ligands that contain hydroxamic or carboxylic acids to chelate the Zn metal. The identification of low molecular weight compounds that contain different scaffolds may lead to the development of a new class of specific inhibitors. 

Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer s disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. 

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