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- Title
Chemical Modifications to Enhance the Drug Properties of a VIP Receptor Antagonist (ANT) Peptide.
- Authors
Lester, Christina; Li, Jian-Ming; Passang, Tenzin; Wang, Yuou; Waller, Edmund K.; Blakey, Simon B.
- Abstract
Antagonist peptides (ANTs) of vasoactive intestinal polypeptide receptors (VIP-Rs) are shown to enhance T cell activation and proliferation in vitro, as well as improving T cell-dependent anti-tumor response in acute myeloid leukemia (AML) murine models. However, peptide therapeutics often suffer from poor metabolic stability and exhibit a short half-life/fast elimination in vivo. In this study, we describe efforts to enhance the drug properties of ANTs via chemical modifications. The lead antagonist (ANT308) is derivatized with the following modifications: N-terminus acetylation, peptide stapling, and PEGylation. Acetylated ANT308 exhibits diminished T cell activation in vitro, indicating that N-terminus conservation is critical for antagonist activity. The replacement of residues 13 and 17 with cysteine to accommodate a chemical staple results in diminished survival using the modified peptide to treat mice with AML. However, the incorporation of the constraint increases survival and reduces tumor burden relative to its unstapled counterpart. Notably, PEGylation has a significant positive effect, with fewer doses of PEGylated ANT308 needed to achieve comparable overall survival and tumor burden in leukemic mice dosed with the parenteral ANT308 peptide, suggesting that polyethylene glycol (PEG) incorporation enhances longevity, and thus the antagonist activity of ANT308.
- Subjects
PEPTIDES; LONGEVITY; VASOACTIVE intestinal peptide; PITUITARY adenylate cyclase activating polypeptide; ACUTE myeloid leukemia; POLYETHYLENE glycol; T cells
- Publication
International Journal of Molecular Sciences, 2024, Vol 25, Issue 8, p4391
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms25084391