Modulation of early aggregation events by flexible peptidomimetics inhibits gelsolin amyloid formation.

Michela Bollati¹, Kaliroi Peqini², Carmina Natale³, Federica Malinverno⁴, Chiara Leonardi⁵, Beatrice Bonaldi², Loic Girois¹, Katiuscia Pagano⁶, Laura Ragona⁶, Alessandro Corbelli³, Fabio Fiordaliso³, Andrea Grazzi⁷, Xinyue Gao⁷, Stefano Pieraccini⁷, Sara Pellegrino², Luisa Diomede³, Matteo de Rosa⁸

¹Institute of Biophysics, National Research Council (IBF-CNR), via A. Corti 12, 20133, Milano, Italy.

²Department of Pharmaceutical Science, "A. Marchesini" General and Organic Chemistry Section, University of Milano, Via Venezian 21, 20133, Milano, Italy.

³Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milano, Italy.

⁴Institute of Biophysics, National Research Council (IBF-CNR), via A. Corti 12, 20133, Milano, Italy; CNR-SCITEC, Institute of Science and Chemical Technologies "Giulio Natta" (SCITEC-CNR), Via Corti 12, 20133, Milano, Italy.

⁵Institute of Biophysics, National Research Council (IBF-CNR), via A. Corti 12, 20133, Milano, Italy; Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milano, Italy.

⁶CNR-SCITEC, Institute of Science and Chemical Technologies "Giulio Natta" (SCITEC-CNR), Via Corti 12, 20133, Milano, Italy.

⁷Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy.

⁸Institute of Biophysics, National Research Council (IBF-CNR), via A. Corti 12, 20133, Milano, Italy. Electronic address: matteo.derosa@cnr.it.

PubMed DOI

Abstract

Gelsolin amyloidosis (Agel) is a hereditary systemic disorder caused by point mutations in the gelsolin (GSN) gene that promote aberrant proteolytic processing and deposition of amyloidogenic fragments. The most prevalent variant, D187N, destabilizes the G2 domain of the protein and exposes a cleavage site, ultimately generating fragments containing the GSN amyloidogenic core. Targeting this seque…

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