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Leveraging Diverse Bi-Triazine Cross-linkers for Modulating Conformation and Biological Activity of Cyclic and Dimeric Peptides
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DOI：10.1021/acs.jmedchem.6c00693.png)
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Abstract
En 中文
Conformational precision is critical for peptide therapeutic design, yet the quantitative link between cross-linker geometry and in vivo performance remains unclear. We present a programmable platform using eight bi-triazine cross-linkers with varied bond length, angle, aromaticity, and symmetry to establish multilevel structure-conformation-biology relationships. Using cyclic RGD peptides targeting integrin alpha v beta 3 and dimeric KTLLPTP peptides targeting Plectin-1 as complementary models, we integrated binding assays, cell studies, and in vivo 68Ga-PET/CT imaging to systematically evaluate linker-induced conformational effects. Two design paradigms emerged: in cyclic peptides, aromaticity and symmetry govern conformational locking, with nonmirror-symmetric naphthalene linkers enhancing protein affinity and tumor uptake. In dimeric systems, bond length and angle enable geometric matching via the molecular ruler effect, with a 120 degrees benzene linker enabling optimal bivalent binding. This work not only identifies the lead candidate [ 68 Ga]Ga-8a with high tumor contrast (similar to 5 %ID/mL) but also provides a generalizable framework for precision peptide engineering.
Keywords:
INTEGRIN
RGD
Journal
IF:
6.8
Papers:
2.7W
Citations:
9.4W