Intrinsically disordered proteins and biomolecular condensates as drug targets |
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Affiliation: | 1. Department of Molecular Medicine, Byrd Alzheimer''s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States;2. Department of Medical Oncology, City of Hope National Medical Center, 1500 Duarte Rd, Duarte, CA, United States |
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Abstract: | Intrinsically disordered domains represent attractive therapeutic targets because they play key roles in cancer, as well as in neurodegenerative and infectious diseases. They are, however, considered undruggable because they do not form stable binding pockets for small molecules and, therefore, have not been prioritized in drug discovery. Under physiological solution conditions many biomedically relevant intrinsically disordered proteins undergo phase separation processes leading to the formation of mesoscopic highly dynamic assemblies, generally known as biomolecular condensates that define environments that can be quite different from the solutions surrounding them. In what follows, we review key recent findings in this area and show how biomolecular condensation can offer opportunities for modulating the activities of intrinsically disordered targets. |
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Keywords: | Intrinsically disordered proteins Biomolecular condensates Free energy landscape Drug discovery |
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