From a Helix to a Small Cycle: Metadynamics‐Inspired αvβ6 Integrin Selective Ligands. Issue 44 (2nd May 2018)

• Record Type: Journal Article
• Authors: Di Leva, Francesco Saverio; Tomassi, Stefano; Di Maro, Salvatore; Reichart, Florian; Notni, Johannes; Dangi, Abha; Marelli, Udaya Kiran; Brancaccio, Diego; Merlino, Francesco; Wester, Hans‐Jürgen; Novellino, Ettore; Kessler, Horst; Marinelli, Luciana
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 44(2018)
• Page Start: 14645
• Page End: 14649
• Publication Date: 2018-05-02
• Subjects: cancer -- drug design -- integrin ligands -- metadynamics -- molecular imaging; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201803250
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: The RGD‐recognizing αvβ6 integrin has only recently emerged as a major target for cancer diagnosis and therapy. Thus, the development of selective, low‐molecular‐weight ligands of this receptor is still in great demand. Here, a metadynamics‐driven design strategy allowed us to successfully convert a helical nonapeptide into a cyclic pentapeptide (6 ) showing remarkable potency and αvβ6 specificity. NMR and docking studies elucidated the reasons for the high affinity and selectivity of this compound, setting the ground for the rational design of new αvβ6‐specific small peptides or even peptidomimetics. In vivo PET imaging studies demonstrated the potential use of6 for medical applications. Abstract : A metadynamics‐driven drug design strategy was employed to transform a helical nonapeptide into a cyclic pentapeptide as a potent and selective ligand of the RGD‐recognizing αvβ6 integrin. This compound was further developed into a PET tracer for specific αvβ6‐mapping in vivo, prompting its use for cancer diagnosis and therapy.