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Highly Potent, Selective, Biostable, and Cell-Permeable Cyclic d-Peptide for Dual-Targeting Therapy of Lung Cancer
Yunjiang Zhou1, Yunting Zou1, Mei Yang1
1Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Abstract:
The application of peptide drugs in cancer therapy is impeded by their poor biostability and weak cell permeability. Therefore, it is imperative to find biostable and cell-permeable peptide drugs for cancer treatment. Here, we identified a potent, selective, biostable, and cell-permeable cyclic d-peptide, NKTP-3, that targets NRP1 and KRASG12D using structure-based virtual screening. NKTP-3 exhibited strong biostability and cellular uptake ability. Importantly, it significantly inhibited the growth of A427 cells with the KRASG12D mutation. Moreover, NKTP-3 showed strong antitumor activity against A427 cell-derived xenograft and KRASG12D-driven primary lung cancer models without obvious toxicity. This study demonstrates that the dual NRP1/KRASG12D-targeting cyclic d-peptide NKTP-3 may be used as a potential chemotherapeutic agent for KRASG12D-driven lung cancer treatment.
Insights
A novel cyclic d-peptide, NKTP-3, shows promise for lung cancer treatment. This biostable peptide targets both Neuropilin-1 (NRP1) and KRAS G12D, effectively inhibiting tumor growth with minimal toxicity.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Peptide drugs face challenges in cancer therapy due to poor biostability and cell permeability.
- Developing stable and cell-penetrating peptide therapeutics is crucial for effective cancer treatment.
Purpose of the Study:
- To identify and characterize a novel cyclic d-peptide with enhanced biostability and cell permeability for cancer therapy.
- To evaluate the therapeutic potential of the identified peptide against KRAS G12D-mutated lung cancer.
Main Methods:
- Structure-based virtual screening was employed to identify potential peptide candidates.
- The identified cyclic d-peptide, NKTP-3, was assessed for its biostability, cellular uptake, and in vitro efficacy against KRAS G12D-mutated cells.
- Antitumor activity and toxicity were evaluated in preclinical models, including xenografts and KRAS G12D-driven primary lung cancer models.
Main Results:
- NKTP-3 demonstrated potent and selective dual targeting of Neuropilin-1 (NRP1) and KRAS G12D.
- The peptide exhibited excellent biostability and cellular uptake capabilities.
- NKTP-3 significantly inhibited the proliferation of A427 cells harboring the KRAS G12D mutation and displayed robust antitumor activity in vivo without significant toxicity.
Conclusions:
- The dual-targeting cyclic d-peptide NKTP-3 is a promising candidate for KRAS G12D-driven lung cancer.
- NKTP-3's favorable biostability and cell permeability offer a potential therapeutic strategy for overcoming current limitations in peptide drug delivery for cancer treatment.
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