Stapled Wasp Venom-Derived Oncolytic Peptides with Side Chains Induce Rapid Membrane Lysis and Prolonged Immune Responses in Melanoma.

Abstract

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 in vivo. 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.

• Authors: Ye Wu, Dong Lu, Yixin Jiang, Jinmei Jin, Sanhong Liu, Lili Chen, Hong Zhang, Yudong Zhou, Hongzhuan Chen, Dale G Nagle, Xin Luan, Weidong Zhang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 9 Pg. 5802-5815 (05 13 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33844923 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Antineoplastic Agents
• Peptides
• Wasp Venoms
• anoplin

Topics

• Amino Acid Sequence
• Animals
• Antimicrobial Cationic Peptides (chemistry)
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• CD8-Positive T-Lymphocytes (cytology, drug effects, immunology)
• Cell Line, Tumor
• Cell Membrane (drug effects, metabolism)
• Drug Design
• Female
• Hydrophobic and Hydrophilic Interactions
• Immunogenic Cell Death (drug effects)
• Immunotherapy
• Melanoma, Experimental (immunology, therapy)
• Mice
• Mice, Inbred BALB C
• Peptides (chemistry, pharmacology, therapeutic use)
• Survival Analysis
• Transplantation, Homologous
• Triple Negative Breast Neoplasms (immunology, therapy)
• Wasp Venoms (chemistry, metabolism)