PDF(Pubmed)
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.
摘要：
血管活性肠多肽受体（VIP-Rs）的拮抗剂肽（ANT）在体外可增强T细胞的活化和增殖，以及改善急性髓系白血病（AML）小鼠模型中T细胞依赖性抗肿瘤反应。然而,肽治疗剂通常具有差的代谢稳定性并且在体内表现出短的半衰期/快速消除。在这项研究中,我们描述了通过化学修饰增强ANTs药物特性的努力。先导拮抗剂（ANT308）通过以下修饰进行衍生化：N端乙酰化，肽装订，和聚乙二醇化。乙酰化ANT308在体外表现出减少的T细胞活化，表明N-末端保守性对于拮抗剂活性至关重要。用半胱氨酸取代残基13和17以适应化学钉导致使用修饰的肽治疗患有AML的小鼠的存活率降低。然而,相对于未钉合的对应物，约束的掺入增加了生存率并减少了肿瘤负担。值得注意的是,聚乙二醇化具有显著的正效应，在给予肠胃外ANT308肽的白血病小鼠中，需要更少的聚乙二醇化ANT308剂量来实现可比的总体生存率和肿瘤负荷，这表明聚乙二醇(PEG)的掺入可以延长寿命，以及ANT308的拮抗剂活性。
