{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T03:28:29Z","timestamp":1771903709193,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T00:00:00Z","timestamp":1608508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["#355866"],"award-info":[{"award-number":["#355866"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003150","name":"Fonds Qu\u00e9b\u00e9cois de la Recherche sur la Nature et les Technologies","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003150","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001805","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001805","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>As a key cytokine mediator of inflammation, interleukin-1\u03b2 (IL-1\u03b2) binds to the IL-1 receptor (IL-1R) and activates various downstream signaling mediators, including NF-\u03baB, which is required for immune vigilance and cellular protection. Toward the development of IL-1-targeting therapeutics which exhibit functional selectivity, the all-D-amino acid peptide <jats:bold>1<\/jats:bold> (101.10, H-D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala-NH<jats:sub>2<\/jats:sub>) was conceived as an allosteric IL-1R modulator that conserves NF-\u03baB signaling while inhibiting other IL-1-activated pathways. Employing \u03b2-hydroxy-\u03b1-amino-\u03b3-lactam (Hgl) stereoisomers to study the conformation about the Thr<jats:sup>3<\/jats:sup> residue in <jats:bold>1<\/jats:bold>, [(3<jats:italic>R<\/jats:italic>,4<jats:italic>S<\/jats:italic>)-Hgl<jats:sup>3<\/jats:sup>]-<jats:bold>1<\/jats:bold> (<jats:bold>2b<\/jats:bold>), among all possible diastereomers, was found to exhibit identical <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> activity as the parent peptide and superior activity to the \u03b1-amino-\u03b3-lactam (Agl) counterpart. Noting the relevance of the \u03b2-hydroxyl substituent and configuration for the activity of (3<jats:italic>R<\/jats:italic>,4<jats:italic>S<\/jats:italic>)-<jats:bold>2b<\/jats:bold>, fifteen different \u03b2-substituted-Agl<jats:sup>3<\/jats:sup> analogs of <jats:bold>1<\/jats:bold> (e.g., <jats:bold>2c-q<\/jats:bold>) have now been synthesized by a combination of solution- and solid-phase methods employing <jats:italic>N<\/jats:italic>-Fmoc-\u03b2-substituted-Agl<jats:sup>3<\/jats:sup>-Val-OH dipeptide building blocks. Introduction of a \u03b2-azido-Agl<jats:sup>3<\/jats:sup> residue into the resin bound peptide and subsequent reduction and CuAAC chemistry gave access to a series of amine and triazole derivatives (e.g., <jats:bold>2h-q<\/jats:bold>). \u03b2-Substituted-[Agl<jats:sup>3<\/jats:sup>]-<jats:bold>1<\/jats:bold> analogs <jats:bold>2c-q<\/jats:bold> exhibited generally similar circular dichroism (CD) spectra as that of Hgl analog <jats:bold>2b<\/jats:bold> in water, presenting curve shapes indicative of \u03b2-turn structures. The relevance of the \u03b2-substituent was indicated in rodent models of preterm labor and retinopathy of prematurity (ROP), in which certain analogs inhibited preterm birth and vaso-obliteration, respectively, with activity similar to <jats:bold>1<\/jats:bold> and <jats:bold>2b<\/jats:bold>. The \u03b2-substituted-[Agl<jats:sup>3<\/jats:sup>]-<jats:bold>1<\/jats:bold> analogs exhibited functional selectivity on IL-1-induced signaling pathways. The described solid-phase method has provided discerning probes for exploring peptide structure-activity relationships and valuable leads for developing prototypes to treat inflammatory events leading to prematurity and retinopathy of prematurity, which are leading causes of infant morbidity and blindness respectively.<\/jats:p>","DOI":"10.3389\/fchem.2020.610431","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T10:48:50Z","timestamp":1608634130000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Interleukin-1 Receptor Modulation Using \u03b2-Substituted \u03b1-Amino-\u03b3-Lactam Peptides From Solid-Phase Synthesis and Diversification"],"prefix":"10.3389","volume":"8","author":[{"given":"Azade","family":"Geranurimi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin W. 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