New therapeutic approaches to osteoporosis: targeting the osteoclast v-atpase

Informations projet

MIVASE

N° de convention de subvention: QLG1-CT-2000-01801

Projet clôturé

Date de début 1 Decembre 2000

Date de fin 30 Novembre 2004

Financé au titre de

• Specific Programme for research, technological development and demonstration on "Quality of life and management of living resources", 1998-2002

Coût total

€ 2 253 153,00

Contribution de l’UE

€ 2 253 153,00

Coordonné par

UNIVERSITY OF LEEDS
United Kingdom

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Livrables

Antibody effective in inhibiting extracellular acidification

Antibodies have been developed which show high specificity towards the specific proteins expressed in osteoblasts and a range of cancer cells. One of these antibodies can inhibit bone resorption due to osteoclasts and the migration of metastatic cancer cells in culture. Patents covering these discoveries are in the process of submission. The results have clear potential for immunotherapeutic approaches to osteoporosis and cancer.

Structural studies have progressed knowledge on the organisation and subunit association of the stalk and membrane sector of the V-H+-ATPase complex

The identification of the binding sites for natural inhibitors of the enzyme complex and the structural characterisation of the proteins involved will both aid targeting and development of compounds for therapeutic intervention. The disposition of proteins in the membrane will further aid the availability of sites of interaction of synthetic compounds.

New compounds have been sysnthesised and developed. They inhibit the vacuolar H+ ATPase and have been useful in both ESR and fluorescence experiments for determining the approximate site on the prote

A range of chemcial compounds have been synthesised which are able to inhibit the enzyme complex. Some represent quite new approaches to interfering with the mechanism of action of the enzyme. These compounds may have value as leads in the development of therapeutic approaches to osteoporosis and cancer.

The new inhibitors have been tested for inhibitory efficacy in yeast and osteoclasts. Assays for the effects in osteoclasts were developed as part of the project

A range of chemcial compounds have been synthesised which are able to inhibit the enzyme complex. Some represent quite new approaches to interfering with the mechanism of action of the enzyme. These compounds may have value as leads in the development of therapeutic approaches to osteoporosis and cancer.

Specific antibodies have been developed which increase our understanding of the topographical arrangement of a major intramembranous subunit

Antibodies have been developed which show high specificity towards the specific proteins expressed in osteoblasts and a range of cancer cells. One of these antibodies can inhibit bone resorption due to osteoclasts and the migration of metastatic cancer cells in culture. Patents covering these discoveries are in the process of submission. The results have clear potential for immunotherapeutic approaches to osteoporosis and cancer.

Cell biological work has revealed the location and processing of the complex and indicated that one of the isoforms of part of the intramembrane proton channel is probably involved in direction

Subunit a3 the largest of the integral membrane proteins which make up the enzyme complex is responsible for targeting the entire complex to the plasma membrane of osteoclasts and tumour cells. This makes the complex available to agents at the outside surface of the cells. This will facilitate the development of strategies for targetting and inhibiting the enzyme and so compromising cell function.