期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 12, 期 4, 页码 585-592出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00636
关键词
1,2,3-Triazoles; peptidomimetics; structure-activity relationships; radiopharmaceuticals; tumor targeting; cancer
资金
- Swiss National Science Foundation [200021-157076]
- Conseil Regional Bourgogne Franche-Comte [2018Y-07062]
- Swiss National Science Foundation (SNF) [200021_157076] Funding Source: Swiss National Science Foundation (SNF)
1,5-Disubstituted 1,2,3-triazoles are bioisosteres of cis-amide bonds and have been shown to enhance pharmacological properties of peptides, particularly in improving receptor binding affinity and tumor uptake as illustrated in this study.
1,5-Disubstituted 1,2,3-triazoles (1,5-Tz) are considered bioisosteres of cis-amide bonds. However, their use for enhancing the pharmacological properties of peptides or proteins is not yet well established. Aiming to illustrate their utility, we chose the peptide conjugate [Nle(15)]MG11 (DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) as a model compound since it is known that the cholecystokinin-2 receptor (CCK2R) is able to accommodate turn conformations. Analogs of [Nle(15)]MG11 incorporating 1,5-Tz in the backbone were synthesized and radiolabeled with lutetium-177, and their pharmacological properties (cell internalization, receptor binding affinity and specificity, plasma stability, and biodistribution) were evaluated and compared with [Nle(15)]MG11 as well as their previously reported analogs bearing 1,4-disubstituted 1,2,3-triazoles. Our investigations led to the discovery of novel triazole-modified analogs of [Nle(15)]MG11 with nanomolar CCK2R-binding affinity and 2-fold increased tumor uptake. This study illustrates that substitution of amides by 1,5-disubstituted 1,2,3-triazoles is an effective strategy to enhance the pharmacological properties of biologically active peptides.
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