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

Abstract

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.

Conformational polymorphism and cellular toxicity of IAPP and βAP domains

“…For example, the proline substitution in the rat IAPP is observed to be a harmless protein. Proteasome inhibitors are currently in clinical trials for the treatment of various cancers (Tan et al, 2006). In light of our results, it is likely that these might result in accumulation of toxic amyloid leading to the slow amyloid related toxic tumor cells.…”

Potential allosteric modulators of the proteasome activity

“…Such diversification of effects of 20S ligands has been observed before. For example, the PA28γ homoheptamer activates only T-L peptidase and fails to affect or inhibits the other peptidases [6,13]. Moreover, the activation-inhibition pattern displayed by PA28γ complex can be switched to the activation pattern resembling PA28αβ actions by a single amino acid residue mutation in PA28γ subunit [13].…”

“…Nevertheless, it would be highly desirable to reach beyond the apoptosis based elimination of cells and gain access to a selective regulation of the proteasome activity, with a precise controlling of gate opening and with enzymatic activity of one type of the active center allosterically influencing performance of other centers [13]. It is conceivable that compounds regulating the proteasome activity in an allosteric manner may offer exactly this type of discriminating capabilities.…”

Rapamycin Allosterically Inhibits the Proteasome

“…Several competitive proteasome inhibitors are used in humans, including two drugs approved by the Food and Drug Administration: bortezomib (Velcade; Millennium Pharmaceuticals, Inc., Cambridge, MA) and carfilzomib (Kyprolis; Onyx Pharmaceuticals, Inc., South San Francisco, CA) (Dick and Fleming, 2010). Apart from cancer, the proteasome is considered a target for anti-inflammatory drugs (Tan et al, 2006).…”