Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Department of Chemistry and Biochemistry, College of Liberal Arts, University of Mississippi, University, Mississippi 38677-1848, United States.
J Med Chem. 2021 May 13;64(9):5802-5815. doi: 10.1021/acs.jmedchem.0c02237. Epub 2021 Apr 12.
Peptide stapling chemistry represents an attractive strategy to promote the clinical translation of protein epitope mimetics, but its use has not been applied to natural cytotoxic peptides (NCPs) to produce new oncolytic peptides. Based on a wasp venom peptide, a series of stapled anoplin peptides (StAnos) were prepared. The optimized stapled Ano-3/3s were shown to be protease-resistant and exerted superior tumor cell-selective cytotoxicity by rapid membrane disruption. In addition, Ano-3/3s induced tumor ablation in mice through the direct oncolytic effect and subsequent stimulation of immunogenic cell death. This synergistic oncolytic-immunotherapy effect is more remarkable on melanoma than on triple-negative breast cancer . The efficacies exerted by Ano-3/3s on melanoma were further characterized by CD8+ T cell infiltration, and the addition of anti-CD8 antibodies diminished the long-term antitumor effects. In summary, these results support stapled peptide chemistry as an advantageous method to enhance the NCP potency for oncolytic therapy.
肽键化学代表了一种有吸引力的策略，可以促进蛋白表位模拟物的临床转化，但尚未将其应用于天然细胞毒性肽（NCPs）以产生新的溶瘤肽。基于一种黄蜂毒液肽，我们制备了一系列订书钉型 anoplin 肽（StAnos）。优化后的订书钉型 Ano-3/3 对蛋白酶具有抗性，并通过快速破坏细胞膜发挥出优异的肿瘤细胞选择性细胞毒性。此外，Ano-3/3 通过直接溶瘤作用和随后刺激免疫原性细胞死亡在小鼠中诱导肿瘤消融。与三阴性乳腺癌相比，这种溶瘤-免疫治疗协同作用在黑色素瘤中更为显著。通过 CD8+ T 细胞浸润进一步表征了 Ano-3/3 对黑色素瘤的作用，添加抗 CD8 抗体减弱了长期抗肿瘤作用。总之，这些结果支持使用订书钉肽化学作为增强 NCP 溶瘤治疗效力的有利方法。
