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

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

  • J Med Chem. 2021 May 13;64(9):5802-5815. doi: 10.1021/acs.jmedchem.0c02237.
Ye Wu 1 Dong Lu 1 Yixin Jiang 1 Jinmei Jin 1 Sanhong Liu 1 Lili Chen 1 Hong Zhang 1 Yudong Zhou 1 2 Hongzhuan Chen 1 Dale G Nagle 1 3 Xin Luan 1 Weidong Zhang 1 4
Affiliations

Affiliations

  • 1 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Department of Chemistry and Biochemistry, College of Liberal Arts, University of Mississippi, University, Mississippi 38677-1848, United States.
  • 3 Department of Biomolecular Sciences and Research of Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677-1848, United States.
  • 4 School of Pharmacy, Second Military Medical University, Shanghai 201203, China.
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.

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