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Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies

1
Department of Molecular Biology and Biotechnology & Department of Biophysics, Biosciences Institute-IB, (UFRGS), Porto Alegre CEP 91501-970, RS, Brazil
2
Center for Biotechnology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre CEP 91501-970, RS, Brazil
3
Graduate Program in Cell and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre CEP 91501-970, RS, Brazil
4
Graduate Program in Medicine and Health Sciences, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 91410-000, RS, Brazil
5
Brain Institute-InsCer, Laboratory of Neurotoxins, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil
6
Department of Pharmaceutical Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre CEP 90050-170, RS, Brazil
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(6), 1322; https://doi.org/10.3390/ijms20061322
Received: 21 December 2018 / Revised: 3 February 2019 / Accepted: 12 February 2019 / Published: 15 March 2019
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Abstract

Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer′s, Parkinson′s, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the “IDP-like” PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases. View Full-Text
Keywords: intrinsically disordered proteins (IDPs); neurodegenerative diseases; aggregation; drugs; drug discovery intrinsically disordered proteins (IDPs); neurodegenerative diseases; aggregation; drugs; drug discovery
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Martinelli, A.H.S.; Lopes, F.C.; John, E.B.O.; Carlini, C.R.; Ligabue-Braun, R. Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies. Int. J. Mol. Sci. 2019, 20, 1322.

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