Highly Potent, Selective, Biostable, and Cell-Permeable Cyclic d-Peptide for Dual-Targeting Therapy of Lung Cancer

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 KRAS^G12D 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 KRAS^G12D mutation. Moreover, NKTP-3 showed strong antitumor activity against A427 cell-derived xenograft and KRAS^G12D-driven primary lung cancer models without obvious toxicity. This study demonstrates that the dual NRP1/KRAS^G12D-targeting cyclic d-peptide NKTP-3 may be used as a potential chemotherapeutic agent for KRAS^G12D-driven lung cancer treatment.