TY - JOUR
T1 - Allosteric regulators of the proteasome
T2 - Potential drugs and a novel approach for drug design
AU - Tan, Xiaolin
AU - Osmulski, Pawel A.
AU - Gaczynska, Maria
PY - 2006/1
Y1 - 2006/1
N2 - 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.
AB - 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.
KW - Allosteric regulator
KW - Drug design
KW - Proteasome
KW - Proteasome inhibitors
KW - Ubiquitin-proteasome pathway
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U2 - 10.2174/092986706775197926
DO - 10.2174/092986706775197926
M3 - Review article
C2 - 16472211
AN - SCOPUS:33645473812
SN - 0929-8673
VL - 13
SP - 155
EP - 165
JO - Current Medicinal Chemistry
JF - Current Medicinal Chemistry
IS - 2
ER -