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Type 2 diabetes (T2D) has recently emerged as a risk factor for PD. Cross\u2010interactions between their amyloidogenic proteins may act as molecular links. In fact, fibrils of islet amyloid polypeptide (IAPP) (T2D) can cross\u2010seed \u03b1Syn amyloidogenesis and \u03b1Syn and IAPP colocalize in PD brains. Inhibition of both self\u2010 and IAPP\u2010cross\u2010seeded \u03b1Syn amyloidogenesis could thus interfere with PD pathogenesis. Here we show that macrocyclic peptides, designed to mimic IAPP self\u2010\/cross\u2010interaction sites and previously found to inhibit amyloidogenesis of IAPP and\/or Alzheimer's disease (AD) amyloid\u2010\u03b2 peptide A\u03b240(42), are nanomolar inhibitors of both self\u2010 and IAPP\u2010cross\u2010seeded amyloid self\u2010assembly of \u03b1Syn. Anti\u2010amyloid function is mediated by nanomolar affinity interactions with \u03b1Syn via three \u03b1Syn regions which are identified as key sites of both \u03b1Syn self\u2010assembly and its cross\u2010interactions with IAPP. We also show that the peptides block A\u03b242\u2010mediated cross\u2010seeding of \u03b1Syn as well. Based on their broad spectrum anti\u2010amyloid function and additional drug\u2010like features, these peptides are leads for multifunctional anti\u2010amyloid drugs in PD, T2D, AD, and their comorbidities, while the identified \u03b1Syn key segments are valuable targets for novel, multi\u2010site targeting amyloid inhibitors in PD and related synucleinopathies.<\/jats:p>","DOI":"10.1002\/anie.202422834","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T09:06:07Z","timestamp":1737104767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi\u2010Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self\u2010 and Cross\u2010Seeded Amyloid Self\u2010Assembly of \u03b1\u2010Synuclein"],"prefix":"10.1002","volume":"64","author":[{"given":"Simon","family":"Hornung","sequence":"first","affiliation":[{"name":"Division of Peptide Biochemistry TUM School of Life Sciences 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