{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:12:56Z","timestamp":1791252776830,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T00:00:00Z","timestamp":1668211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH Office Research Infrastructure Programs","award":["P40 OD010440"],"award-info":[{"award-number":["P40 OD010440"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gelsolin amyloidosis (AGel) is characterized by multiple systemic and ophthalmic features resulting from pathological tissue deposition of the gelsolin (GSN) protein. To date, no cure is available for the treatment of any form of AGel. More than ten single-point substitutions in the GSN gene are responsible for the occurrence of the disease and, among them, D187N\/Y is the most widespread variant. These substitutions undergo an aberrant proteolytic cascade, producing aggregation-prone peptides of 5 and 8 kDa, containing the Gelsolin Amyloidogenic Core, spanning residues 182\u2013192 (GAC182\u2013192). Following a structure-based approach, we designed and synthesized three novel sequence-specific peptidomimetics (LB-5, LB-6, and LB-7) built on a piperidine-pyrrolidine unnatural amino acid. LB-5 and LB-6, but not LB-7, efficiently inhibit the aggregation of the GAC182\u2013192 amyloidogenic peptides at sub-stoichiometric concentrations. These peptidomimetics resulted also effective in vivo, in a C. elegans-based assay, in counteracting the proteotoxicity of aggregated GAC182\u2013192. These data pave the way to a novel pharmacological strategy against AGel and also validate a toolbox exploitable in other amyloidogenic diseases.<\/jats:p>","DOI":"10.3390\/ijms232213973","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:29:32Z","timestamp":1668392972000},"page":"13973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Rational Design of a Peptidomimetic Inhibitor of Gelsolin Amyloid Aggregation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6579-2043","authenticated-orcid":false,"given":"Michela","family":"Bollati","sequence":"first","affiliation":[{"name":"Institute of Biophysics, National Research Council (IBF-CNR), c\/o Department of Biosciences, University of Milano, Via Celoria 26, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaliroi","family":"Peqini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, \u201cA. Marchesini\u201d General and Organic Chemistry Section, University of Milano, Via Venezian 21, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Barone","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, \u201cA. Marchesini\u201d General and Organic Chemistry Section, University of Milano, Via Venezian 21, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmina","family":"Natale","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7201-6704","authenticated-orcid":false,"given":"Marten","family":"Beeg","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1014-6225","authenticated-orcid":false,"given":"Marco","family":"Gobbi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-0531","authenticated-orcid":false,"given":"Luisa","family":"Diomede","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelangelo","family":"Trucchi","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, National Research Council (IBF-CNR), c\/o Department of Biosciences, University of Milano, Via Celoria 26, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-5426","authenticated-orcid":false,"given":"Matteo","family":"de Rosa","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, National Research Council (IBF-CNR), c\/o Department of Biosciences, University of Milano, Via Celoria 26, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-3583","authenticated-orcid":false,"given":"Sara","family":"Pellegrino","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, \u201cA. Marchesini\u201d General and Organic Chemistry Section, University of Milano, Via Venezian 21, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13023-020-1300-5","article-title":"Finnish Gelsolin Amyloidosis Causes Significant Disease Burden but Does Not Affect Survival: FIN-GAR Phase II Study","volume":"15","author":"Schmidt","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"506","DOI":"10.3109\/07853890.2015.1075063","article-title":"Natural Course of Finnish Gelsolin Amyloidosis","volume":"47","author":"Nikoskinen","year":"2015","journal-title":"Ann. 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