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Allosteric Regulators of the Proteasome: Potential Drugs and a Novel Approach for Drug Design

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The proteasome recently gained an exceptional attention as a novel drug target, therefore its inhibitors became important subjects for rational drug design. A synthetic competitive inhibitor Velcade was lately approved in a fast-track process to treat multiple myeloma and is tested with other types of cancers. The proteasome is a major proteolytic assembly in eukaryotic cells responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and apoptosis. The ubiquitin-proteasome pathway has been implicated in many diseases such as cancer, autoimmune diseases, inflammation, and stroke. The activity of the proteasome can be blocked for therapeutic purposes with competitive inhibitors like Velcade, which trigger apoptosis in target cells. However, much more versatile outcomes and a true control of the proteasome can be achieved with allosteric regulators. Certain natural proteins and peptides bind to the catalytic core of the proteasome and allosterically induce a wide array of effects ranging from changes in product size to substrate-specific inhibition. Designing small synthetic compounds allosterically interacting with the proteasome represents a novel approach that has enormous potential for the treatment of a wide range of diseases. Below we provide a review of current knowledge about proteasomal allosteric ligands.
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Keywords: Proteasome; allosteric regulator; drug design; proteasome inhibitors; ubiquitin-proteasome pathway

Document Type: Research Article

Affiliations: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, USA.

Publication date: 2006-01-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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