Ansamer-Controlled Bicyclic Peptides as Integrin αvβ6 Targeting Agents.
Bicyclic peptides just got more interesting. Researchers led by Yang and colleagues have shown that ansamer-controlled bicyclic peptides can lock into distinct shapes (Pansa and Mansa) that don't flip back and forth, opening up new angles for targeting tough proteins like integrins. Their focus: engineering these peptides to zero in on integrin αvβ6, a surface protein with big implications for cancer research.
Angew Chem Int Ed Engl
by Yang H, Dong W, An Y et al.
“Ansamer-Controlled Bicyclic Peptides as Integrin αvβ6 Targeting Agents. Yang H(1), Dong W(2), An Y(3), He Z(4), Pan H(2), Pan W(2), Tan J(2), Sun J(2), Shen C(2), Su W(2), Wang J(3), Süssmuth RD(4), Yao G(1)(2). Author information: (1)School of Life Sciences, Fudan University, Shanghai, China. (2)Greater Bay Area Institute of Precision Medicine, Guangzhou, China. (3)School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. (4)Institut Für Chemie, Technische Universität Berlin, Berlin, Germany. Bicyclic peptides are promising candidates for peptide-drug conjugates due to their structural rigidity and high target specificity. Recently, it became more apparent that some peptides form nonclassical conformational isomers, termed ansamers. These conformational isomers designated as Pansa and Mansa are non-interconvertible and separable, thus broaden the chemical space of the peptide template. In this study, we incorporated the RGD motif into a bicyclic peptide and systematically assessed the inhibitory activities of the Pansa and Mansa isomers against various integrins. The molecule 10-Mansa exhibited high selectivity and potent inhibitory activity against the αvβ6 integrin, whereas 10-Pansa, its conformational counterpart, lacked such activity. The cryo-EM structure of αvβ6 bound to 10-Mansa shows, that it adopts a conformation with the cyclohexane sidechain of the amino acid Chg engaging in hydrophobic interactions with Ile183 and the disulfide bond within the β6 SDL2 loop. Compared to the linear peptide A20FMDV, a broadly applied αvβ6 inhibitor, 10-Mansa displays faster cellular internalization and also sustains prolonged enrichment within tumor tissues. Moreover, employing 10-Mansa a designed toxin-drug conjugate exhibits remarkable tumor-suppressing effects in vivo. These findings reveal how conformational isomers of ansamers affect biological activity-and highlight their potential for the identification of new bioactive molecules. © 2026 Wiley‐VCH GmbH.”
Here’s what stands out. The team inserted the classic RGD motif, known for its integrin-grabbing power, into a carefully designed bicyclic peptide. They then separated out the Pansa and Mansa isomers—two flavors of the same molecule, each stuck in its own conformation. Turns out, only the Mansa version (specifically, 10-Mansa) showed potent and selective inhibition of αvβ6. The Pansa isomer? No dice.
Structural work using cryo-EM revealed why: 10-Mansa’s unique shape lets it tuck a cyclohexane sidechain right into a hydrophobic pocket on the αvβ6 integrin, forming tight contacts that its counterpart can’t replicate. Compared to the classic linear peptide inhibitor A20FMDV, this bicyclic design isn’t just stickier—it’s faster at getting into cells and hangs around longer in tumor tissue.
Key takeaway:
Ansamer isomerism isn’t just chemical trivia. It’s a lever for tuning peptide activity and selectivity.
10-Mansa, when linked to a toxin payload, shows strong tumor suppression in vivo—a promising route for future peptide-drug conjugates.
This is a big win for anyone interested in expanding the possibilities of peptide research. Expect to see more targeted, shape-controlled peptides powering the next wave of bioactive molecule discovery.
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