{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T22:36:37Z","timestamp":1790980597602,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Emory School of Medicine","award":["I3C Catalyst Grant"],"award-info":[{"award-number":["I3C Catalyst Grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms25084391","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T08:22:44Z","timestamp":1713342164000},"page":"4391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Chemical Modifications to Enhance the Drug Properties of a VIP Receptor Antagonist (ANT) Peptide"],"prefix":"10.3390","volume":"25","author":[{"given":"Christina","family":"Lester","sequence":"first","affiliation":[{"name":"Department of Chemistry, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Ming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenzin","family":"Passang","sequence":"additional","affiliation":[{"name":"Cancer Biology Graduate Program, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-8055","authenticated-orcid":false,"given":"Yuou","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmund K.","family":"Waller","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4100-8610","authenticated-orcid":false,"given":"Simon B.","family":"Blakey","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1304336","DOI":"10.1080\/2162402X.2017.1304336","article-title":"Administration of a vasoactive intestinal peptide antagonist enhances the autologous anti-leukemia T cell response in murine models of acute leukemia","volume":"6","author":"Petersen","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1182\/blood-2021-151879","article-title":"Inhibition of Vasoactive Intestinal Peptide Signaling with More Potent Inhibitors Augments T Cell Activation and Prolongs Survival in Leukemic Mice","volume":"138","author":"Fnu","year":"2021","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1124\/pr.56.2.7","article-title":"The significance of vasoactive intestinal peptide in immunomodulation","volume":"56","author":"Delgado","year":"2004","journal-title":"Pharmacol. 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