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The 26S Proteasome : A New Target for Drug Discovery

Objective

The objectives of the proposed studies are to use biochemical, protein structural, enzymological and molecular biological techniques together with the power of yeast genetics to characterise fully the intracellular protease called the 26S proteasome. The information gained in the programme will form the basis for the design and development of compounds which have great therapeutic potential for a variety of acute and chronic human and animal diseases.

The 26S proteasome is the major intracellular non-lysosomal protease involved in the degradation of proteins. The 26S proteasome works in part in conjunction with the cellular protein ubiquitination and ubiquitination systems. The combined proteolytic systems serve to continually degrade cellular proteins. The ubiquitin/26S proteasome system is critical for the regulated degradation of transcription factors, cell cycle regulators, and the generation of protein fragments for class 1 antigen presentation in addition to regulating the general degradation of many cellular proteins The 26S proteasomeis composed of a proteolytic 20S cylindrical core together with regulatory subunits. There are two types of regulatory complex, the 19S and 1 1 S regulators. These regulators sit on the ends of the cylindrical core and regulate the access and degradation of target proteins. The consortium will study the structure and function of the ATPases and the non-ATPases which are part of the 19S regulating complexes of the 26S proteasome. Developmental control of the regulatory subunits in model systems and in human tissues will be central to the studies. Additionally, the power of yeast genetics will be employed in order to understand the phenotypes generated by mutations in the ATPase and non-ATPase regulators. Phenotypic changes in the higher eukaryotic cells will be studied by the application of antisense technology. The mechanisms of assembly of the 19S regulatory complexes and association with the 20S core will also be studied. The properties of the 26S proteasome will be explored in models of neuromuscular degeneration and protein catabolic disease. Our pharmaceutical collaborator will make available archive chemicals. together with new combinatorial libraries of compounds. which will be evaluated in in vitro and in vivo assay systems (for efficacy in inhibiting and modulating the activity of the 26S proteasome). Expressed recombinant regulators of the 26S proteasome will be used in in vitro reconstitution experiments with 20S proteasomes protein in assays for the evaluation of lead compounds. The studies will lead to the synthesis of lead compounds which will be efficacious in the treatment of cancer (cell cycle dysfunction and apoptosis), inflammation (antigen processing) and muscular protein wasting (e.g. metabolic acidosis).

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

University of Nottingham
Address
Univ. Of Nottingham
NG7 2UH Nottingham
United Kingdom

Participants (7)

Ciba-Geigy Ltd.
Switzerland
Address
Giba-geigy Ltd
4002 Basle
Commissariat à l'Energie Atomique
France
Address
Ctr Etudes De Saclay - Ce-s
91192 Gif-sur-yvette
Deutsche Diabetes Forschungsgesellschaft e.V.
Germany
Address
65,Auf'm-hennekamp
40225 Dusseldorf
Humboldt-Universität zu Berlin
Germany
Address
3-4,Hessische Str
10115 Berlin
MEDICAL RESEARCH COUNCIL
United Kingdom
Address
Crewe Road Western General Hospital
EH4 2XU Edinburgh
Universität Stuttgart
Germany
Address
55,Pfaffenwaldring
70569 Stuttgart
Université de Clermont-Ferrand II (Université Blaise Pascal)
France
Address

63177 Aubière