Synthetic Peptides with Genetic‐Codon‐Tailored Affinity for Assembling Tetraspanin CD81 at Cell Interfaces and Inhibiting Cancer Metastasis

The first peptidyl ligand targeting the intrinsically disordered region of tetraspanin CD81 has been identified. By forming steric complementarity with CD81, the peptide enables in situ tracking of the dynamic distribution of CD81 at cell-contact interfaces. Further blockage of cell migration highlights the key role of the target motif of CD81 in cell communication, which presents the peptide as a functional inhibitor against cancer growth and metastasis.

Abstract

Probing biomolecular interactions at cellular interfaces is crucial for understanding and interfering with life processes. Although affinity binders with site specificity for membrane proteins are unparalleled molecular tools, a high demand remains for novel multi-functional ligands. In this study, a synthetic peptide (APQQ) with tight and specific binding to the untargeted extracellular loop of CD81 evolved from a genetically encoded peptide pool. With tailored affinity, APQQ flexibly accesses, site-specifically binds, and forms a complex with CD81, enabling in-situ tracking of the dynamics and activity of this protein in living cells, which has rarely been explored because of the lack of ligands. Furthermore, APQQ triggers the relocalization of CD81 from diffuse to densely clustered at cell junctions and modulates the interplay of membrane proteins at cellular interfaces. Motivated by these, efficient suppression of cancer cell migration, and inhibition of breast cancer metastasis were achieved in vivo.

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