1. A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease
- Author
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Francesco Simone Ruggeri, Michele Perni, Michele Vendruscolo, Christian P. Haas, Francesco A. Aprile, Christopher M. Dobson, Thomas C. T. Michaels, Gabriella T. Heller, Tatsuya Ikenoue, Tuomas P. J. Knowles, Benedetta Mannini, Pietro Sormanni, Ryan Limbocker, Christoph Middel, Sormanni, Pietro [0000-0002-6228-2221], Ruggeri, Francesco [0000-0002-1232-1907], Knowles, Tuomas [0000-0002-7879-0140], Vendruscolo, Michele [0000-0002-3616-1610], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Amyloid ,In silico ,lcsh:Medicine ,Plaque, Amyloid ,Peptide ,010402 general chemistry ,Protein Aggregation, Pathological ,01 natural sciences ,Epitope ,Article ,03 medical and health sciences ,Alzheimer Disease ,Animals ,631/92 ,Life Science ,Caenorhabditis elegans ,lcsh:Science ,Binding selectivity ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Multidisciplinary ,Bicyclic molecule ,Drug discovery ,lcsh:R ,Rational design ,631/154 ,Small molecule ,Chemical biology ,Peptide Fragments ,In vitro ,0104 chemical sciences ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Biochemistry ,lcsh:Q - Abstract
Funder: Centre for Misfolding Diseases, Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.
- Published
- 2020