Abstract
Bicyclic peptides, which integrate the advantageous properties of small molecules and antibodies, have emerged as a promising class of therapeutic candidates. In particular, integrin αvβ3 serves as a critical molecular target for cancer diagnosis and therapy. However, the development of bicyclic peptide ligands specifically targeting this integrin remains inadequately explored. To address this gap, we designed and synthesized a series of RGD-containing bicyclic peptides featuring a tryptathionine bridge. Notably, bicyclic peptide 5j incorporates the non-canonical sequence norArg-Gly-Asp, exhibiting high affinity and selectivity toward integrin αvβ3. Molecular dynamics simulations provided insights into the conformational preferences and demonstrated that norArg plays a critical role in determining the selectivity between αvβ3 and αIIbβ3. Employing peptide 5j as the targeting ligand, the peptide drug conjugates P1 showed significant inhibitory effects on the A549 cell line in both, in vitro and in vivo experiments. These data provide important theoretical foundations for the development of αvβ3-targeting bicyclic peptides and offer new options for αvβ3-targeted tumor therapy.
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This work was supported by the National Natural Science Foundation of China (grants 82204189) and Guangdong Basic and Applied Basic Research Foundation (2022A1515111207).
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H.Y., H.P., and T. R. contributed equally to this work. H.Y. synthesized the target compounds, completed HPLC analysis and performed partial biological assays. H.P., W.D., and J.T. completed most biological assays and analyzed part of the data. W.P. performed the pharmacokinetic experiments. T. R. performed the theoretical calculations and molecular docking. G.Y., W.S., R.D.S., and J.S. proposed the project. G.Y., R.D.S., and H.Y. performed data analysis and contributed to the writing-review and editing of the manuscript. All authors have given approval to the final version of the manuscript.
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Yang, H., Pan, H., Ran, T. et al. Identification of an αvβ3-targeting bicyclic peptide with atypical norArg-Gly-Asp sequence. Commun Chem (2026). https://doi.org/10.1038/s42004-026-01886-y
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DOI: https://doi.org/10.1038/s42004-026-01886-y
