{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["16(36)"],"submitter":["O'Brien EA"],"pubmed_abstract":["Amidines are a relatively unexplored isostere of the amide bond, offering unique electronic properties and hydrogen-bonding behavior. This study presents the first systematic investigation of amidines within folded β-sheet structures. Using CD, NMR, and aggregation assays, we find that amidines are well tolerated when acting as hydrogen-bond donors but disrupt β-sheet folding when serving as hydrogen-bond acceptors. This donor/acceptor asymmetry contrasts with the behavior of amidines in α-helices, where both roles are accommodated. Importantly, outward-facing amidines disrupt the edge-to-edge hydrogen bonding required for fibril formation, enabling the design of non-aggregating β-hairpin peptidomimetics without reliance on sequence charge. Spectroscopic analysis further reveals that amidines embedded in peptide backbones exist predominantly in their neutral, monoprotonated form even at acidic pH, prompting a reassessment of amidine basicity in structured biomolecules. These findings establish design principles for using amidines in stable, aggregation-resistant peptidomimetic scaffolds."],"journal":["Chemical science"],"pagination":["16970-16978"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12379966"],"repository":["biostudies-literature"],"pubmed_title":["The 'ins' and 'outs' of amidines in β-sheet folding and fibril disaggregation."],"pmcid":["PMC12379966"],"pubmed_authors":["Purslow JA","Abbasi M","VanVeller B","O'Brien EA"],"additional_accession":[]},"is_claimable":false,"name":"The 'ins' and 'outs' of amidines in β-sheet folding and fibril disaggregation.","description":"Amidines are a relatively unexplored isostere of the amide bond, offering unique electronic properties and hydrogen-bonding behavior. This study presents the first systematic investigation of amidines within folded β-sheet structures. Using CD, NMR, and aggregation assays, we find that amidines are well tolerated when acting as hydrogen-bond donors but disrupt β-sheet folding when serving as hydrogen-bond acceptors. This donor/acceptor asymmetry contrasts with the behavior of amidines in α-helices, where both roles are accommodated. Importantly, outward-facing amidines disrupt the edge-to-edge hydrogen bonding required for fibril formation, enabling the design of non-aggregating β-hairpin peptidomimetics without reliance on sequence charge. Spectroscopic analysis further reveals that amidines embedded in peptide backbones exist predominantly in their neutral, monoprotonated form even at acidic pH, prompting a reassessment of amidine basicity in structured biomolecules. These findings establish design principles for using amidines in stable, aggregation-resistant peptidomimetic scaffolds.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-02T20:34:02.589Z","creation":"2026-05-27T03:08:00.333Z"},"accession":"S-EPMC12379966","cross_references":{"pubmed":["40880782"],"doi":["10.1039/d5sc05902j"]}}