2. Academic Validation
  3. Identification of an αvβ3-targeting bicyclic peptide with atypical norArg-Gly-Asp sequence

Identification of an αvβ3-targeting bicyclic peptide with atypical norArg-Gly-Asp sequence

  • Commun Chem. 2026 Jan 12;9(1):83. doi: 10.1038/s42004-026-01886-y.
Haijian Yang # 1,  Hui Pan # 2,  Ting Ran # 3,  Wenyan Dong 2,  Wencong Pan 2,  Jianhui Tan 2,  Jingjing Sun 4,  Roderich D Süssmuth 5,  Wu Su 6,  Guiyang Yao 7 8
Affiliations

Affiliations

  • 1 School of Life Sciences, Fudan University, Shanghai, China.
  • 2 Center for Innovative Drug Discovery, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou, China.
  • 3 Division of drug and vaccine research, Guangzhou National Laboratory, Guangzhou, China.
  • 4 Center for Innovative Drug Discovery, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou, China. [email protected].
  • 5 Institut für Chemie, Technische Universität Berlin, Berlin, Germany. [email protected].
  • 6 Center for Innovative Drug Discovery, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou, China. [email protected].
  • 7 School of Life Sciences, Fudan University, Shanghai, China. [email protected].
  • 8 Center for Innovative Drug Discovery, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41526498 DOI: 10.1038/s42004-026-01886-y
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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