{"entity": "researcher", "timestamp": "2026-08-20T21:12:21.983Z", "family": "Sk\u00f6ld", "given": "Christian", "initials": "C", "orcid": "0000-0001-5235-2559", "affiliations": ["Department of Medicinal Chemistry, BMC Uppsala University P.O. Box 574 SE-751 23 Uppsala Sweden luke.odell@ilk.uu.se."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/4a0f6301615d4ca797404fcb84151565.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/4a0f6301615d4ca797404fcb84151565"}}, "publications": [{"entity": "publication", "iuid": "269a603509824100bff3124d33b60066", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/269a603509824100bff3124d33b60066.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/269a603509824100bff3124d33b60066"}}, "title": "Novel macrocyclic peptidomimetics targeting the insulin-regulated aminopeptidase (IRAP): design, synthesis and evaluation.", "authors": [{"family": "Olaniran H\u00e5kansson", "given": "Esther", "initials": "E", "orcid": "0009-0008-6737-0336", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/16479ef00dcb48728df9174e0e446219.json"}}, {"family": "Balestri", "given": "Lorenzo J I", "initials": "LJI"}, {"family": "Puthiyaparambath", "given": "Sharathna", "initials": "S"}, {"family": "Moes", "given": "Sebastian", "initials": "S"}, {"family": "Henschel", "given": "Henning", "initials": "H", "orcid": "0000-0001-7196-661X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bc7be8d4d25240d2bb63f020653a50c3.json"}}, {"family": "Sk\u00f6ld", "given": "Christian", "initials": "C", "orcid": "0000-0001-5235-2559", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4a0f6301615d4ca797404fcb84151565.json"}}, {"family": "Hallberg", "given": "Mathias", "initials": "M"}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Skillinghaug", "given": "Bobo", "initials": "B", "orcid": "0000-0002-8014-5757", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e4d7881ac9b6431d8eb0b0e319d9cd82.json"}}, {"family": "Odell", "given": "Luke R", "initials": "LR", "orcid": "0000-0001-7658-5103", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/49395660c6af4fce9ad0f7f8fc793744.json"}}], "type": "journal article", "published": "2025-10-15", "journal": {"title": "RSC Med Chem", "issn": "2632-8682", "volume": "16", "issue": "10", "pages": "5059-5069", "issn-l": null}, "abstract": "Inhibition of the insulin-regulated aminopeptidase (IRAP) is a promising therapeutic strategy for neurodegenerative disorders such as Alzheimer's disease, due to its role in cognitive processes. HA08, a macrocyclic peptidomimetic derived from angiotensin IV, is among the most potent known IRAP inhibitors (IC50 = 18 nM). However, detailed structure-activity relationship (SAR) studies at its C-terminus have been limited by synthetic constraints. Herein, we report the design, synthesis, and biological evaluation of a focused series of HA08 analogues to explore the impact of C-terminal modifications on IRAP inhibition. An improved divergent synthetic route was established via a common macrocyclic intermediate, enabling late-stage diversification through coupling with non-natural amino acids which led to the synthesis of twelve novel peptidomimetic scaffolds. Several analogues retained high potency, with one-carbon elongation next to the carboxylic acid moiety or secondary amine being well tolerated. In contrast, aliphatic analogues exhibited markedly reduced potency, highlighting the importance of \u03c0-\u03c0 interactions, while the low activity of phenoxyacetic acid derivatives likely reflects altered geometry within the binding pocket. The most potent inhibitor in the series featured a C-terminal benzyl alcohol (IC50 = 59 nM), approaching the activity of HA08. To rationalise these SAR trends, molecular dynamics simulations were performed based on the IRAP-HA08 co-crystal structure. Partial least squares analysis of protein-ligand contact patterns revealed that sustained interactions between the C-terminal carboxylate and Arg929 correlated with lower potency, whereas interaction with Arg439 was associated with enhanced activity. These findings suggest that subtle shifts in C-terminal positioning influence binding mode and potency and provides valuable insights for the design of future IRAP inhibitors.", "doi": "10.1039/d5md00438a", "pmid": "40881305", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12378631"}, {"db": "pii", "key": "d5md00438a"}], "notes": [], "created": "2026-08-20T09:28:09.435Z", "modified": "2026-08-20T09:28:09.628Z"}]}