{"entity": "researcher", "timestamp": "2026-08-20T20:28:18.115Z", "family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "affiliations": ["Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f"}}, "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"}, {"entity": "publication", "iuid": "5a1cabc3966c4bfc9331c7a709676084", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/5a1cabc3966c4bfc9331c7a709676084.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/5a1cabc3966c4bfc9331c7a709676084"}}, "title": "Benzylhydroxamic Acids as IRAP Inhibitors: Sulfonamide Variations", "authors": [{"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/35360120fcd544faba8998acdcc6d5bc.json"}}, {"family": "Beveridge", "given": "Julia", "initials": "J", "orcid": "0000-0002-9425-8832", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f24567000ef3421286eb1f019071cac3.json"}}, {"family": "S\u00f6derstr\u00f6m", "given": "Marcus", "initials": "M"}, {"family": "Balestri", "given": "Lorenzo Jacopo Ilic", "initials": "LJI"}, {"family": "Prieto-D\u00edaz", "given": "Rub\u00e9n", "initials": "R"}, {"family": "Gutierrez-de-Teran", "given": "Hugo", "initials": "H"}, {"family": "Odell", "given": "Luke R", "initials": "LR", "orcid": "0000-0001-7658-5103", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/49395660c6af4fce9ad0f7f8fc793744.json"}}, {"family": "Hallberg", "given": "Mathias", "initials": "M"}], "type": "journal-article", "published": "2025-10-00", "journal": {"title": "Synlett", "issn": "0936-5214", "volume": "36", "issue": "16", "pages": "2666-2670", "issn-l": null}, "abstract": null, "doi": "10.1055/a-2562-7204", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T09:28:35.950Z", "modified": "2026-08-20T09:28:36.052Z"}, {"entity": "publication", "iuid": "e28e0ff6eea04d33b55d4d01075bcfac", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e28e0ff6eea04d33b55d4d01075bcfac.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e28e0ff6eea04d33b55d4d01075bcfac"}}, "title": "A Diastereoselective Mizoroki\u2013Heck Reaction for Synthesis of Spirooxindole-Based Nonnatural Amino Acids Using a Boc-Protected Amine Chiral Auxiliary", "authors": [{"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Lindman", "given": "Jens", "initials": "J"}, {"family": "Puthiyaparambath", "given": "Sharathna", "initials": "S"}, {"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/35360120fcd544faba8998acdcc6d5bc.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": "2025-09-00", "journal": {"title": "Synlett", "issn": "0936-5214", "volume": "36", "issue": "14", "pages": "2009-2013", "issn-l": null}, "abstract": null, "doi": "10.1055/a-2564-4920", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T09:28:37.751Z", "modified": "2026-08-20T09:28:37.840Z"}, {"entity": "publication", "iuid": "c54b915ee83742c09ee7121dc8dec5a5", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/c54b915ee83742c09ee7121dc8dec5a5.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/c54b915ee83742c09ee7121dc8dec5a5"}}, "title": "Inhibition of IRAP Enhances the Expression of Pro-Cognitive Markers Drebrin and MAP2 in Rat Primary Neuronal Cells.", "authors": [{"family": "Stam", "given": "Frida", "initials": "F"}, {"family": "Bjurling", "given": "Sara", "initials": "S"}, {"family": "Nylander", "given": "Erik", "initials": "E", "orcid": "0000-0002-9683-6034", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6c44bdb91fce4b53ac2eff374bbf9c00.json"}}, {"family": "H\u00e5kansson", "given": "Esther Olaniran", "initials": "EO"}, {"family": "Barlow", "given": "Nicholas", "initials": "N", "orcid": "0000-0002-5749-3542", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a67b60d6fd4048d6b34766c0dfc82547.json"}}, {"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/35360120fcd544faba8998acdcc6d5bc.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Odell", "given": "Luke R", "initials": "LR"}, {"family": "Gr\u00f6nbladh", "given": "Alfhild", "initials": "A", "orcid": "0000-0001-9780-4168", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/43805f4c399d4ba9b6a3e62a5081cef2.json"}}, {"family": "Hallberg", "given": "Mathias", "initials": "M", "orcid": "0000-0002-9835-870X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/76184702a3c14996a2ab9db8ffdbe19f.json"}}], "type": "journal article", "published": "2024-11-08", "journal": {"title": "Int J Mol Sci", "issn": "1422-0067", "volume": "25", "issue": "22", "issn-l": null}, "abstract": "The insulin-regulated aminopeptidase (IRAP; oxytocinase) is part of the M1 aminopeptidase family and is highly expressed in many tissues, including the neocortex and hippocampus of the brain. IRAP is involved in various physiological functions and has been identified as a receptor for the endogenous hexapeptide Angiotensin IV (Ang IV). The binding of Ang IV inhibits the enzymatic activity of IRAP and has been proven to enhance learning and memory in animal models. The macrocyclic compound 9 (C9) is a potent synthetic IRAP inhibitor developed from the previously reported inhibitor HA08. In this study, we have examined compound C9 and its effects on cognitive markers drebrin, microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP) in primary hippocampal and cortical cultures. Cells from Sprague Dawley rats were cultured for 14 days before treatment with C9 for 4 consecutive days. The cells were analysed for protein expression of drebrin, MAP2, GFAP, glucose transporter type 4 (GLUT4), vesicular glutamate transporter 1 (vGluT1), and synapsin I using immunocytochemistry. The gene expression of related proteins was determined using qPCR, and viability assays were performed to evaluate toxicity. The results showed that protein expression of drebrin and MAP2 was increased, and the corresponding mRNA levels were decreased after treatment with C9 in the hippocampal cultures. The ratio of MAP2-positive neurons and GFAP-positive astrocytes was altered and there were no toxic effects observed. In conclusion, the IRAP inhibitor compound C9 enhances the expression of the pro-cognitive markers drebrin and MAP2, which further confirms IRAP as a relevant pharmaceutical target and C9 as a promising candidate for further investigation.", "doi": "10.3390/ijms252212016", "pmid": "39596085", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11594062"}, {"db": "pii", "key": "ijms252212016"}], "notes": [], "created": "2026-08-20T13:41:58.326Z", "modified": "2026-08-20T13:41:58.446Z"}, {"entity": "publication", "iuid": "1888a6a69811421c88b2f0f897864384", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/1888a6a69811421c88b2f0f897864384.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/1888a6a69811421c88b2f0f897864384"}}, "title": "Inhibition of IRAP Enhance the Expression of Pro-cognitive Markers Drebrin and MAP2 in Rat Primary Neuronal Cells", "authors": [{"family": "Stam", "given": "Frida", "initials": "F"}, {"family": "Bjurling", "given": "Sara", "initials": "S"}, {"family": "Nylander", "given": "Erik", "initials": "E"}, {"family": "Olaniran H\u00e5kansson", "given": "Esther", "initials": "E"}, {"family": "Barlow", "given": "Nicholas", "initials": "N", "orcid": "0000-0002-5749-3542", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a67b60d6fd4048d6b34766c0dfc82547.json"}}, {"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/35360120fcd544faba8998acdcc6d5bc.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Odell", "given": "Luke R", "initials": "LR"}, {"family": "Gr\u00f6nbladh", "given": "Alfhild", "initials": "A"}, {"family": "Hallberg", "given": "Mathias", "initials": "M"}], "type": "posted-content", "published": "2024-07-31", "journal": {"issn-l": null}, "abstract": null, "doi": "10.20944/preprints202407.2523.v1", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T12:56:40.055Z", "modified": "2026-08-20T12:56:40.138Z"}, {"entity": "publication", "iuid": "3c64f59b59394580bc404609d7606bed", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3c64f59b59394580bc404609d7606bed.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3c64f59b59394580bc404609d7606bed"}}, "title": "The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds.", "authors": [{"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/35360120fcd544faba8998acdcc6d5bc.json"}}, {"family": "Honarnejad", "given": "Saman", "initials": "S", "orcid": "0000-0002-4558-501X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/138a2199f9504b9fa96c3c963e820b21.json"}}, {"family": "Bras", "given": "Maaike", "initials": "M"}, {"family": "Baillie", "given": "Gemma L", "initials": "GL"}, {"family": "McElroy", "given": "Stuart P", "initials": "SP", "orcid": "0000-0002-5182-2616", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6c4e720e5e2946ecb4d2d32ea12818a6.json"}}, {"family": "Jones", "given": "Philip S", "initials": "PS"}, {"family": "Morrison", "given": "Angus", "initials": "A"}, {"family": "Beveridge", "given": "Julia", "initials": "J", "orcid": "0000-0002-9425-8832", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f24567000ef3421286eb1f019071cac3.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"}}], "type": "journal article", "published": "2024-04-06", "journal": {"title": "Int J Mol Sci", "issn": "1422-0067", "volume": "25", "issue": "7", "issn-l": null}, "abstract": "With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 \u00b5M. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.", "doi": "10.3390/ijms25074084", "pmid": "38612894", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11012289"}, {"db": "pii", "key": "ijms25074084"}], "notes": [], "created": "2026-08-20T13:41:47.032Z", "modified": "2026-08-20T13:41:47.226Z"}, {"entity": "publication", "iuid": "346c4ade3b754191842578052e228656", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/346c4ade3b754191842578052e228656.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/346c4ade3b754191842578052e228656"}}, "title": "Hydrogen Peroxide Induced Toxicity Is Reversed by the Macrocyclic IRAP-Inhibitor HA08 in Primary Hippocampal Cell Cultures.", "authors": [{"family": "Stam", "given": "Frida", "initials": "F"}, {"family": "Flor\u00e9n Lind", "given": "Sara", "initials": "S"}, {"family": "Schroff", "given": "Anja", "initials": "A"}, {"family": "Zelleroth", "given": "Sofia", "initials": "S"}, {"family": "Nylander", "given": "Erik", "initials": "E", "orcid": "0000-0002-9683-6034", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6c44bdb91fce4b53ac2eff374bbf9c00.json"}}, {"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/35360120fcd544faba8998acdcc6d5bc.json"}}, {"family": "Gr\u00f6nbladh", "given": "Alfhild", "initials": "A", "orcid": "0000-0001-9780-4168", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/43805f4c399d4ba9b6a3e62a5081cef2.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Hallberg", "given": "Mathias", "initials": "M", "orcid": "0000-0002-9835-870X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/76184702a3c14996a2ab9db8ffdbe19f.json"}}], "type": "journal article", "published": "2022-10-18", "journal": {"title": "Curr Issues Mol Biol", "issn": "1467-3045", "volume": "44", "issue": "10", "pages": "5000-5012", "issn-l": null}, "abstract": "Angiotensin IV (Ang IV), a metabolite of Angiotensin II, is a bioactive hexapeptide that inhibits the insulin-regulated aminopeptidase (IRAP). This transmembrane zinc metallopeptidase with many biological functions has in recent years emerged as a new pharmacological target. IRAP is expressed in a variety of tissues and can be found in high density in the hippocampus and neocortex, brain regions associated with cognition. Ang IV is known to improve memory tasks in experimental animals. One of the most potent IRAP inhibitors known today is the macrocyclic compound HA08 that is significantly more stable than the endogenous Ang IV. HA08 combines structural elements from Ang IV and the physiological substrates oxytocin and vasopressin, and binds to the catalytic site of IRAP. In the present study we evaluate whether HA08 can restore cell viability in rat primary cells submitted to hydrogen peroxide damage. After damaging the cells with hydrogen peroxide and subsequently treating them with HA08, the conceivable restoring effects of the IRAP inhibitor were assessed. The cellular viability was determined by measuring mitochondrial activity and lactate dehydrogenase (LDH) release. The mitochondrial activity was significantly higher in primary hippocampal cells, whereas the amount of LDH was unaffected. We conclude that the cell viability can be restored in this cell type by blocking IRAP with the potent macrocyclic inhibitor HA08, although the mechanism by which HA08 exerts its effects remains unclear.", "doi": "10.3390/cimb44100340", "pmid": "36286055", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9601255"}, {"db": "pii", "key": "cimb44100340"}], "notes": [], "created": "2026-08-20T13:40:22.494Z", "modified": "2026-08-20T13:40:22.656Z"}, {"entity": "publication", "iuid": "72ee9eefd35a4eb5a621db013223e75a", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/72ee9eefd35a4eb5a621db013223e75a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/72ee9eefd35a4eb5a621db013223e75a"}}, "title": "Synthesis and In Vitro Biological Evaluation of Quinolinyl Pyrimidines Targeting Type II NADH-Dehydrogenase (NDH-2).", "authors": [{"family": "Lu", "given": "Lu", "initials": "L"}, {"family": "\u00c5kerbladh", "given": "Linda", "initials": "L"}, {"family": "Ahmad", "given": "Shabbir", "initials": "S"}, {"family": "Konda", "given": "Vivek", "initials": "V"}, {"family": "Cao", "given": "Sha", "initials": "S"}, {"family": "Vocat", "given": "Anthony", "initials": "A"}, {"family": "Maes", "given": "Louis", "initials": "L"}, {"family": "Cole", "given": "Stewart T", "initials": "ST"}, {"family": "Hughes", "given": "Diarmaid", "initials": "D"}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Brandt", "given": "Peter", "initials": "P"}, {"family": "Karl\u00e9n", "given": "Anders", "initials": "A"}, {"family": "Mowbray", "given": "Sherry L", "initials": "SL", "orcid": "0000-0002-0732-6367", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/93f59b3d476e43f1bdf90e120e92e165.json"}}], "type": "journal article", "published": "2022-03-11", "journal": {"title": "ACS Infect Dis", "issn": "2373-8227", "volume": "8", "issue": "3", "pages": "482-498", "issn-l": "2373-8227"}, "abstract": "Type II NADH dehydrogenase (NDH-2) is an essential component of electron transfer in many microbial pathogens but has remained largely unexplored as a potential drug target. Previously, quinolinyl pyrimidines were shown to inhibit Mycobacterium tuberculosis NDH-2, as well as the growth of the bacteria [Shirude, P. S.; ACS Med. Chem. Lett. 2012, 3, 736-740]. Here, we synthesized a number of novel quinolinyl pyrimidines and investigated their properties. In terms of inhibition of the NDH-2 enzymes from M. tuberculosis and Mycobacterium smegmatis, the best compounds were of similar potency to previously reported inhibitors of the same class (half-maximal inhibitory concentration (IC50) values in the low-\u03bcM range). However, a number of the compounds had much better activity against Gram-negative pathogens, with minimum inhibitory concentrations (MICs) as low as 2 \u03bcg/mL. Multivariate analyses (partial least-squares (PLS) and principle component analysis (PCA)) showed that overall ligand charge was one of the most important factors in determining antibacterial activity, with patterns that varied depending on the particular bacterial species. In some cases (e.g., mycobacteria), there was a clear correlation between the IC50 values and the observed MICs, while in other instances, no such correlation was evident. When tested against a panel of protozoan parasites, the compounds failed to show activity that was not linked to cytotoxicity. Further, a strong correlation between hydrophobicity (estimated as clog P) and cytotoxicity was revealed; more hydrophobic analogues were more cytotoxic. By contrast, antibacterial MIC values and cytotoxicity were not well correlated, suggesting that the quinolinyl pyrimidines can be optimized further as antimicrobial agents.", "doi": "10.1021/acsinfecdis.1c00413", "pmid": "35184552", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8922281"}], "notes": [], "created": "2026-08-20T08:10:15.537Z", "modified": "2026-08-20T08:10:15.644Z"}, {"entity": "publication", "iuid": "53a49c26113a49c7b81046171f734e46", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/53a49c26113a49c7b81046171f734e46.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/53a49c26113a49c7b81046171f734e46"}}, "title": "Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer-Optimization of the Affinity towards PSMA by Linker Modification in Murine Model.", "authors": [{"family": "Lundmark", "given": "Fanny", "initials": "F", "orcid": "0000-0002-9153-2832", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c6690e6a499c48e98f5c7f6038bb463c.json"}}, {"family": "Abouzayed", "given": "Ayman", "initials": "A"}, {"family": "Mitran", "given": "Bogdan", "initials": "B"}, {"family": "Rinne", "given": "Sara S", "initials": "SS"}, {"family": "Varasteh", "given": "Zohreh", "initials": "Z"}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Tolmachev", "given": "Vladimir", "initials": "V", "orcid": "0000-0002-6122-1734", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/896ae9fae8b74251afe11b4354c62794.json"}}, {"family": "Rosenstr\u00f6m", "given": "Ulrika", "initials": "U", "orcid": "0000-0002-0817-8140", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ec6820fcb786475d85969630b0b3860b.json"}}, {"family": "Orlova", "given": "Anna", "initials": "A", "orcid": "0000-0001-6120-2683", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1c374f429702489494c05f84f298b4b7.json"}}], "type": "journal article", "published": "2020-07-01", "journal": {"title": "Pharmaceutics", "issn": "1999-4923", "volume": "12", "issue": "7", "issn-l": null}, "abstract": "Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets could be beneficial. Recently, our group reported the novel heterodimer BQ7800 consisting of a urea-based PSMA inhibitor, the peptide-based GRPR antagonist RM26 and NOTA chelator. The study reported herein, aimed to improve the affinity of BQ7800 towards PSMA by changing the composition of the two linkers connecting the PSMA- and GRPR-targeting motifs. Three novel heterodimeric analogues were synthesized by incorporation of phenylalanine in the functional linker of the PSMA-binding motif and/or shortening the PEG-linker coupled to RM26. The heterodimers were labeled with indium-111 and evaluated in vitro. In the competitive binding assay, BQ7812, featuring phenylalanine and shorter PEG-linker, demonstrated a nine-fold improved affinity towards PSMA. In the in vivo biodistribution study of [111In]In-BQ7812 in PC3-pip tumor-bearing mice (PSMA and GRPR positive), the activity uptake was two-fold higher in the tumor and three-fold higher in kidneys than for [111In]In-BQ7800. Herein, we showed that the affinity of a bispecific PSMA/GRPR heterodimer towards PSMA could be improved by linker modification.", "doi": "10.3390/pharmaceutics12070614", "pmid": "32630176", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC7408065"}, {"db": "pii", "key": "pharmaceutics12070614"}], "notes": [], "created": "2026-08-20T13:42:59.018Z", "modified": "2026-08-20T13:42:59.116Z"}, {"entity": "publication", "iuid": "62b65b338e974d0b82eef298d4c72699", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/62b65b338e974d0b82eef298d4c72699.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/62b65b338e974d0b82eef298d4c72699"}}, "title": "Regio- and Stereoselective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via an Intramolecular Mizoroki-Heck Reaction.", "authors": [{"family": "Adeyemi", "given": "Ahmed", "initials": "A"}, {"family": "Odell", "given": "Luke R", "initials": "LR", "orcid": "0000-0001-7658-5103", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/49395660c6af4fce9ad0f7f8fc793744.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}], "type": "journal article", "published": "2020-06-19", "journal": {"title": "J. Org. Chem.", "issn": "1520-6904", "volume": "85", "issue": "12", "pages": "7648-7657", "issn-l": "0022-3263"}, "abstract": "The palladium(0)-catalyzed intramolecular annulation of 12 1,3-disubstituted cyclopentenes, derived from (+)-vince lactam, resulted in 5-exo cyclizations which furnished a series of 2,5-dimethyl-1-((3R,4'S)-2H-spiro[benzofuran-3,1'-cyclopentan]-2'-en-4'-yl)-1H-pyrroles in excellent diastereoselectivities and useful isolated yields. The double bond migration process that followed the arylpalladium insertion was controlled by a fine-tuning of the reaction system, which provided regioselectivities of up to 98:2. The selective Mizoroki-Heck reaction was used as the key transformation for preparing two new spirocyclic monoprotected amino acids as single stereoisomers.", "doi": "10.1021/acs.joc.9b03329", "pmid": "32083867", "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T08:10:58.675Z", "modified": "2026-08-20T08:10:58.752Z"}, {"entity": "publication", "iuid": "347e12b5e010425cae36b0a03d10b72e", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/347e12b5e010425cae36b0a03d10b72e.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/347e12b5e010425cae36b0a03d10b72e"}}, "title": "Macrocyclic peptidomimetics as inhibitors of insulin-regulated aminopeptidase (IRAP).", "authors": [{"family": "Barlow", "given": "Nicholas", "initials": "N", "orcid": "0000-0002-5749-3542", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a67b60d6fd4048d6b34766c0dfc82547.json"}}, {"family": "Vanga", "given": "Sudarsana Reddy", "initials": "SR"}, {"family": "S\u00e4vmarker", "given": "Jonas", "initials": "J"}, {"family": "Sandstr\u00f6m", "given": "Anja", "initials": "A"}, {"family": "Burns", "given": "Peta", "initials": "P"}, {"family": "Hallberg", "given": "Anders", "initials": "A"}, {"family": "\u00c5qvist", "given": "Johan", "initials": "J"}, {"family": "Guti\u00e9rrez-de-Ter\u00e1n", "given": "Hugo", "initials": "H"}, {"family": "Hallberg", "given": "Mathias", "initials": "M", "orcid": "0000-0002-9835-870X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/76184702a3c14996a2ab9db8ffdbe19f.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Chai", "given": "Siew Yeen", "initials": "SY", "orcid": "0000-0001-7209-4112", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1ed844df0afe48c3928a8707886ec681.json"}}, {"family": "Thompson", "given": "Philip E", "initials": "PE", "orcid": "0000-0002-5910-7625", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8d855f9d000e43b1afa8f07d062c8c8a.json"}}], "type": "journal article", "published": "2020-02-01", "journal": {"title": "RSC Med Chem", "issn": "2632-8682", "volume": "11", "issue": "2", "pages": "234-244", "issn-l": null}, "abstract": "Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (\u0394G) and relative binding free energies (\u0394\u0394G) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.", "doi": "10.1039/c9md00485h", "pmid": "33479630", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC7412577"}, {"db": "pii", "key": "c9md00485h"}], "notes": [], "created": "2026-08-20T09:27:13.786Z", "modified": "2026-08-20T09:27:13.994Z"}, {"entity": "publication", "iuid": "f231ab25ca63453aabd43fca29e1bc82", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/f231ab25ca63453aabd43fca29e1bc82.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/f231ab25ca63453aabd43fca29e1bc82"}}, "title": "Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer.", "authors": [{"family": "Mitran", "given": "Bogdan", "initials": "B"}, {"family": "Varasteh", "given": "Zohreh", "initials": "Z"}, {"family": "Abouzayed", "given": "Ayman", "initials": "A"}, {"family": "Rinne", "given": "Sara S", "initials": "SS"}, {"family": "Puuvuori", "given": "Emmi", "initials": "E"}, {"family": "De Rosa", "given": "Maria", "initials": "M", "orcid": "0000-0002-4087-2554", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0723571cbae046a3b06daacced710bd9.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Tolmachev", "given": "Vladimir", "initials": "V", "orcid": "0000-0002-6122-1734", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/896ae9fae8b74251afe11b4354c62794.json"}}, {"family": "Orlova", "given": "Anna", "initials": "A", "orcid": "0000-0001-6120-2683", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1c374f429702489494c05f84f298b4b7.json"}}, {"family": "Rosenstr\u00f6m", "given": "Ulrika", "initials": "U", "orcid": "0000-0002-0817-8140", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ec6820fcb786475d85969630b0b3860b.json"}}], "type": "journal article", "published": "2019-09-14", "journal": {"title": "Cancers (Basel)", "issn": "2072-6694", "volume": "11", "issue": "9", "issn-l": "2072-6694"}, "abstract": "Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging of PCa. The heterodimer NOTA-DUPA-RM26 was produced by manual solid-phase peptide synthesis. NOTA-DUPA-RM26 was labeled with 111In and 68Ga, with yields >98%, and demonstrated a high stability and binding specificity to PSMA and GRPR. IC50 values for natIn-NOTA-DUPA-RM26 were 4 \u00b1 1 nM towards GRPR and 824 \u00b1 230 nM towards PSMA. An in vivo binding specificity 1 h pi of 111In-NOTA-DUPA-RM26 in PC3-PIP-xenografted mice demonstrated partially blockable tumor uptake when co-injected with an excess of PSMA- or GRPR-targeting agents. Simultaneous co-injection of both agents induced pronounced blocking. The biodistribution of 111In-NOTA-DUPA-RM26 and 68Ga-NOTA-DUPA-RM26 revealed fast activity clearance from the blood and normal organs via the kidneys. Tumor uptake exceeded normal organ uptake for both analogs 1 h pi. 68Ga-NOTA-DUPA-RM26 had a significantly lower tumor uptake (8 \u00b1 2%ID/g) compared to 111In-NOTA-DUPA-RM26 (12 \u00b1 2%ID/g) 1 h pi. Tumor-to-organ ratios increased 3 h pi, but decreased 24 h pi, for 111In-NOTA-DUPA-RM26. MicroPET/CT and microSPECT/CT scans confirmed biodistribution data, suggesting that 68Ga-NOTA-DUPA-RM26 and 111In-NOTA-DUPA-RM26 are suitable candidates for the imaging of GRPR and PSMA expression in PCa shortly after administration.", "doi": "10.3390/cancers11091371", "pmid": "31540122", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC6771040"}, {"db": "pii", "key": "cancers11091371"}], "notes": [], "created": "2026-08-20T13:39:15.966Z", "modified": "2026-08-20T13:39:16.126Z"}, {"entity": "publication", "iuid": "72a8c3b95b674cf186a9698113f12544", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/72a8c3b95b674cf186a9698113f12544.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/72a8c3b95b674cf186a9698113f12544"}}, "title": "Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer.", "authors": [{"family": "Abouzayed", "given": "Ayman", "initials": "A"}, {"family": "Yim", "given": "Cheng-Bin", "initials": "CB"}, {"family": "Mitran", "given": "Bogdan", "initials": "B"}, {"family": "Rinne", "given": "Sara S", "initials": "SS"}, {"family": "Tolmachev", "given": "Vladimir", "initials": "V", "orcid": "0000-0002-6122-1734", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/896ae9fae8b74251afe11b4354c62794.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Rosenstr\u00f6m", "given": "Ulrika", "initials": "U"}, {"family": "Orlova", "given": "Anna", "initials": "A", "orcid": "0000-0001-6120-2683", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1c374f429702489494c05f84f298b4b7.json"}}], "type": "journal article", "published": "2019-07-23", "journal": {"title": "Pharmaceutics", "issn": "1999-4923", "volume": "11", "issue": "7", "issn-l": null}, "abstract": "Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)8 (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [125I]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [125I]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [125I]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%-35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [125I]I-BO530 is a promising agent for theranostics application in prostate cancer.", "doi": "10.3390/pharmaceutics11070358", "pmid": "31340483", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC6680768"}, {"db": "pii", "key": "pharmaceutics11070358"}], "notes": [], "created": "2026-08-20T13:42:56.984Z", "modified": "2026-08-20T13:42:57.066Z"}, {"entity": "publication", "iuid": "228c270ef8604a678b31a76a83de35b4", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/228c270ef8604a678b31a76a83de35b4.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/228c270ef8604a678b31a76a83de35b4"}}, "title": "Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki\u2013Heck Coupling of Aryl Iodides", "authors": [{"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/225695195abc4233bd141e6858e72e7f.json"}}, {"family": "Adeyemi", "given": "Ahmed", "initials": "A"}, {"family": "Wetzel", "given": "Alexander", "initials": "A"}, {"family": "Bergman", "given": "Joakim", "initials": "J"}, {"family": "Br\u00e5nalt", "given": "Jonas", "initials": "J"}], "type": "journal-article", "published": "2019-01-00", "journal": {"title": "Synlett", "issn": "0936-5214", "volume": "30", "issue": "01", "pages": "82-88", "issn-l": null}, "abstract": null, "doi": "10.1055/s-0037-1611360", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T09:28:41.627Z", "modified": "2026-08-20T09:28:41.704Z"}]}