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ABSTRACT 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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS RAPID DISCOVERY OF CYCLIC PEPTIDE PROTEIN AGGREGATION INHIBITORS BY CONTINUOUS SELECTION Article 13 January 2025 PROTEIN

MIMETIC 2D FAST RESCUES ALPHA SYNUCLEIN AGGREGATION MEDIATED EARLY AND POST DISEASE PARKINSON’S PHENOTYPES Article Open access 30 April 2024 A RAPID IN VIVO PIPELINE TO IDENTIFY SMALL

MOLECULE INHIBITORS OF AMYLOID AGGREGATION Article Open access 27 September 2024 CHANGE HISTORY * _ 02 JANUARY 2018 In the version of this Article originally published, in Fig. 1c–e, on the

x axes, the lines labelled ‘Aβ42’ and ‘Aβ42(F19S;L34P)’ grouped the data incorrectly; the line labelled Aβ42 should have grouped the data for Random 1–2 and Clones 1–10, and the line

labelled Aβ42(F19S;L34P) should have only grouped the data for Random 1–2 on the right end of the plots and blots. These figures have now been corrected in all versions of the Article. _

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affinities. _Expert Opin. Drug Dis._ 10, 449–461 (2015). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank S. Benkovic (Penn State University) and M. H.

Hecht (Princeton University) for the plasmids, D. Walsh (Brigham and Women’s Hospital), L. Stefanis (University of Athens) and M. Paravatou-Petsotas (National Center for Scientific Research

'Demokritos') for the cell lines, C. D. Link (University of Colorado Boulder) for the _C. elegans_ CL2331 strain and P. Mehta (Institute for Basic Research in Developmental

Disabilities) for the antibodies. The nematode strains used in this study were provided by the Caenorhabditis Genetics Center, supported by the United States National Institutes of Health

National Center for Research Resources. We also thank D. Gialama for technical assistance with the initial expression vector construction and E. Megalou for bacterial sample preparations for

the _C. elegans_ feeding assays. We gratefully acknowledge G. Georgiou (University of Texas at Austin) for facilitating the flow cytometric sorting experiments and V. Papadimitriou and A.

Xenakis for the dynamic light scattering experiments. 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. AUTHOR INFORMATION Author notes * Konstantinos D. Papavasileiou

Present address: Institute of Nanoscience and Nanotechnology, National Center for Scientific Research “Demokritos”, 15310, Athens, Greece AUTHORS AND AFFILIATIONS * Institute of Biology,

Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635, Athens, Greece Ilias Matis, Dafni Chrysanthi Delivoria, Nikoletta Papaevgeniou, Stefania Panoutsou, 

Stamatia Bellou, Konstantinos D. Papavasileiou, Zacharoula I. Linardaki, Efstathios S. Gonos, Manthos G. Papadopoulos, Niki Chondrogianni & Georgios Skretas * School of Chemical

Engineering, National Technical University of Athens, 15780, Athens, Greece Ilias Matis, Dafni Chrysanthi Delivoria & Fragiskos N. Kolisis * Institute of Biosciences and Applications,

National Center for Scientific Research “Demokritos”, 15310, Athens, Greece Barbara Mavroidi & Maria Pelecanou * Faculty of Biology and Pharmacy, Institute of Nutrition, Friedrich

Schiller University of Jena, 07743, Jena, Germany Nikoletta Papaevgeniou * Department of Biology, National and Kapodistrian University of Athens, 15701, Athens, Greece Stefania Panoutsou, 

Alexandra V. Stavropoulou & Spiros Efthimiopoulos * Department of Biology, University of Patras, 26504, Patras, Greece Zacharoula I. Linardaki & Marigoula Margarity * Department of

Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece Kostas Vekrellis * Institute of Nanoscience and Nanotechnology,

National Center for Scientific Research “Demokritos”, 15310, Athens, Greece Nikos Boukos * Medical School, Örebro University, 70182, Örebro, Sweden Efstathios S. Gonos Authors * Ilias Matis

View author publications You can also search for this author inPubMed Google Scholar * Dafni Chrysanthi Delivoria View author publications You can also search for this author inPubMed Google

Scholar * Barbara Mavroidi View author publications You can also search for this author inPubMed Google Scholar * Nikoletta Papaevgeniou View author publications You can also search for

this author inPubMed Google Scholar * Stefania Panoutsou View author publications You can also search for this author inPubMed Google Scholar * Stamatia Bellou View author publications You

can also search for this author inPubMed Google Scholar * Konstantinos D. Papavasileiou View author publications You can also search for this author inPubMed Google Scholar * Zacharoula I.

Linardaki View author publications You can also search for this author inPubMed Google Scholar * Alexandra V. Stavropoulou View author publications You can also search for this author

inPubMed Google Scholar * Kostas Vekrellis View author publications You can also search for this author inPubMed Google Scholar * Nikos Boukos View author publications You can also search

for this author inPubMed Google Scholar * Fragiskos N. Kolisis View author publications You can also search for this author inPubMed Google Scholar * Efstathios S. Gonos View author

publications You can also search for this author inPubMed Google Scholar * Marigoula Margarity View author publications You can also search for this author inPubMed Google Scholar * Manthos

G. Papadopoulos View author publications You can also search for this author inPubMed Google Scholar * Spiros Efthimiopoulos View author publications You can also search for this author

inPubMed Google Scholar * Maria Pelecanou View author publications You can also search for this author inPubMed Google Scholar * Niki Chondrogianni View author publications You can also

search for this author inPubMed Google Scholar * Georgios Skretas View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS G.S. conceived and

coordinated the project. G.S., N.C., M.P., K.D.P. and S.E. designed the research. G.S., E.S.G., M.P., S.E., M.M., K.V., N.C. and F.N.K. attracted funding. I.M., D.C.D., B.M., N.P., S.P.,

S.B., K.D.P., Z.I.L., A.V.S., N.B., K.V. and G.S. performed the research. I.M., D.C.D., B.M., N.P., S.P., S.B., K.D.P., Z.I.L., K.V., S.E., M.P., N.C. and G.S. analysed the data. G.S., N.C.,

M.P., Ν.Β., K.V., S.E. and M.G.P. supervised the research. G.S. wrote the paper with contributions from I.M., D.C.D., B.M., N.P., S.P., K.D.P., Z.I.L., S.E., N.C. and M.P. All authors read

and approved the final version of the paper. CORRESPONDING AUTHOR Correspondence to Georgios Skretas. ETHICS DECLARATIONS COMPETING INTERESTS G.S. is the inventor on patent applications for

AβC5-34, AβC5-116, SOD1C5-4 and other Aβ- and SOD1-targeting peptide macrocyclic sequences described in this article. ADDITIONAL INFORMATION PUBLISHER’S NOTE: Springer Nature remains neutral

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ARTICLE CITE THIS ARTICLE Matis, I., Delivoria, D.C., Mavroidi, B. _et al._ An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding.

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