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Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease
Open AccessArticle

New Peptide-Based Pharmacophore Activates 20S Proteasome

1
Department of Molecular Medicine, UT Health San Antonio, Texas, TX 78245, USA
2
Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, Texas, TX 78245, USA
3
Department of Organic Chemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland
4
Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland
5
Southwest Research Institute, San Antonio, Texas, TX 78238, USA
6
The Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, TX 78229, USA
*
Authors to whom correspondence should be addressed.
Current address: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Academic Editors: Jetze J. Tepe and Derek J. McPhee
Molecules 2020, 25(6), 1439; https://doi.org/10.3390/molecules25061439
Received: 7 January 2020 / Revised: 13 March 2020 / Accepted: 18 March 2020 / Published: 22 March 2020
(This article belongs to the Special Issue Proteasome Regulators: Activators and Inhibitors)
The proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively unexplored. In this work, we introduce short TAT peptides derived from HIV-1 Tat protein and modified with synthetic turn-stabilizing residues as proteasome agonists. Molecular docking and biochemical studies point to the α1/α2 pocket of the core proteasome α ring as the binding site of TAT peptides. We postulate that the TATs’ pharmacophore consists of an N-terminal basic pocket-docking “activation anchor” connected via a β turn inducer to a C-terminal “specificity clamp” that binds on the proteasome α surface. By allosteric effects—including destabilization of the proteasomal gate—the compounds substantially augment activity of the core proteasome in vitro. Significantly, this activation is preserved in the lysates of cultured cells treated with the compounds. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use. View Full-Text
Keywords: proteasome; activation; allostery; peptides; beta turn; proteasome dynamics; atomic force microscopy proteasome; activation; allostery; peptides; beta turn; proteasome dynamics; atomic force microscopy
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MDPI and ACS Style

Osmulski, P.A.; Karpowicz, P.; Jankowska, E.; Bohmann, J.; Pickering, A.M.; Gaczyńska, M. New Peptide-Based Pharmacophore Activates 20S Proteasome. Molecules 2020, 25, 1439.

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