Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding
Δημιουργός/Συγγραφέας:	Matis I. Delivoria D.C. Mavroidi B. Papaevgeniou N. Panoutsou S. Bellou S. Papavasileiou K.D. Linardaki Z.I. Stavropoulou A.V. Vekrellis K. Boukos N. [EL] Κολίσης, Φραγκίσκος Ν.[EN] Kolisis, Fragiskos N.‏ [EL] Γκόνος, Ευστάθιος[EN] Gonos, Efstathios S. Margarity M. [EL] Παπαδόπουλος, Μάνθος Γ.[EN] Papadopoulos, Manthos G. Efthimiopoulos S. Pelecanou M. [EL] Χονδρογιάννη, Νίκη[EN] Chondrogianni, Niki [EL] Σκρέτας, Γιώργος[EN] Skretas, George
Εκδότης:	Nature Publishing Group
Ημερομηνία:	2017
Γλώσσα:	Αγγλικά
ISSN:	2157-846X
DOI:	10.1038/s41551-017-0144-3
Άλλο:	PubMed ID: 31015593
Περίληψη:	Protein misfolding and aggregation are common pathological features of several human diseases, including Alzheimer's disease and type 2 diabetes. Here, we report an integrated and generalizable bacterial system for the facile discovery of chemical rescuers of disease-associated protein misfolding. In this system, large combinatorial libraries of macrocyclic molecules are biosynthesized in Escherichia coli cells and simultaneously screened for their ability to rescue pathogenic protein misfolding and aggregation using a flow cytometric assay. We demonstrate the effectiveness of this approach by identifying drug-like, head-to-tail cyclic peptides that modulate the aggregation of the Alzheimer's disease-associated amyloid β peptide. Biochemical, biophysical and biological assays using isolated amyloid β peptide, primary neurons and various established Alzheimer's disease nematode models showed that the selected macrocycles potently inhibit the formation of neurotoxic amyloid β peptide aggregates. We also applied the system to the identification of misfolding rescuers of mutant Cu/Zn superoxide dismutase-an enzyme linked with inherited forms of amyotrophic lateral sclerosis. Overall, the system enables the identification of molecules with therapeutic potential for rescuing the misfolding of disease-associated polypeptides.
Τίτλος πηγής δημοσίευσης:	Nature Biomedical Engineering
Τόμος/Κεφάλαιο:	1
Τεύχος:	10
Σελίδες:	838-852
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General)
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2017 The Author(s).
Σημειώσεις:	pr001017; RI-261600; FP7 Research infrastructures, INFRASTRUCTURES; State Scholarships Foundation, IKY; General Secretariat for Research and Technology, GSRT; John S. Latsis Public Benefit Foundation; National Health Research Institutes; Siemens; Ministry of Education, Lifelong Learning and Religious Affairs. This work was funded by the following projects: NEUROTHERAPY in the framework of the research grant 'Aristeia', financed by the Hellenic General Secretariat of Research and Technology and the National Strategic Reference Framework (to G.S.); CYCLIPAD in the framework of the research grant 'Thalis', financed by the Hellenic Ministry of Education, Research and Religious Affairs and the National Strategic Reference Framework (to E.S.G., G.S., F.N.K., M.P., M.M. and S.E.); the John S. Latsis Public Benefit Foundation (to N.C. and G.S.); and the Synthetic Biology research infrastructure OMIC-ENGINE, financed by the Hellenic General Secretariat of Research and Technology and the National Strategic Reference Framework. S.B. and Z.I.L. are recipients of fellowships for post-doctoral research by the Hellenic State Scholarships Foundation "IKY Fellowships of Excellence for Postgraduate Studies in Greece - Siemens Program". The Graphics Processing Unit (GPU)-accelerated molecular dynamics simulations were performed at the LinkSCEEM Cy-Tera GPU cluster, supported by the LinkSCEEM-2 project and funded by the European Union FP7 Capacities Research Infrastructure, INFRA-2010-1.2.3 Virtual Research Communities (grant agreement RI-261600). The molecular mechanics Poisson–Boltzmann surface area calculations were supported by computational time granted by the Greek Research and Technology Network in the National High Performance Computing Facility Advanced Research Information System under project identification pr001017.
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο