{
  "abstract": "Peptide sequence modification and lipidation are key chemical strategies for extending the therapeutic exposure of glucagon-like peptide-1 (GLP-1) receptor agonists, but the biophysical mechanisms underlying their persistence in circulation warrant further investigation. We investigated how α-aminoisobutyric acid (Aib) substitution and C16-to-C18 acyl-chain extension affect the biophysical properties, functional potency, and preservation of activity of liraglutide analogues. These two modifications are found in semaglutide whose dosing schedule is once weekly in contrast to once daily for liraglutide. The unmodified liraglutide was compared with three variants incorporating Aib substitution, chain extension, or both. Dynamic light scattering and circular dichroism showed similar apparent hydrodynamic radii and broadly similar secondary-structure profiles among the liraglutide constructs under the measurement conditions. In cell-based cyclic AMP (cAMP) assays, chain extension increased the half-maximal effective concentration from 193 to 847 pM, corresponding to approximately 4.4-fold lower apparent functional potency. After 48 h of dipeptidyl peptidase-4 (DPP4) exposure in phosphate-buffered saline, constructs without Aib showed substantial response losses in the cAMP assay, whereas Aib containing variants retained high responses. Human serum preserved responses across all four constructs during DPP4 exposure. These results distinguish the potency cost of chain extension from Aib-associated preservation of activity during enzymatic challenge and serum-dependent retention of responses. They support combining sequence modifications that resist enzymatic inactivation with lipidation that preserves functional potency in the design of longer-acting GLP-1 therapeutics.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry and Biochemistry, University of North Carolina Wilmington, 601 S College Rd, Wilmington, NC, 28403"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rickey Su",
      "orcid": "0009-0009-4187-3194"
    },
    {
      "name": "Lev P. Oykhman",
      "orcid": "0009-0006-3381-5785"
    },
    {
      "name": "Ying Wang",
      "orcid": "0000-0001-6370-4134"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/f583fdwt264n3.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15011100/v1",
  "fulltext_url": null,
  "id": "f583fdwt264n3",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011100/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2712|Diabetes Treatment and Management"
    ]
  ],
  "openalex": "W7223935287",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15011100/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-27",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/f583fdwt264n3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15011100",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011100/v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Diabetes Treatment and Management",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Effects of Aib Substitution and Acyl Chain Extension on Liraglutide Biophysical Properties and Functional Activity",
  "title_text": "Effects of Aib Substitution and Acyl Chain Extension on Liraglutide Biophysical Properties and Functional Activity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/f583fdwt264n3",
  "venue": "ChemRxiv",
  "versions": []
}