Premium
From a Helix to a Small Cycle: Metadynamics‐Inspired αvβ6 Integrin Selective Ligands
Author(s) -
Di Leva Francesco Saverio,
Tomassi Stefano,
Di Maro Salvatore,
Reichart Florian,
Notni Johannes,
Dangi Abha,
Marelli Udaya Kiran,
Brancaccio Diego,
Merlino Francesco,
Wester HansJürgen,
Novellino Ettore,
Kessler Horst,
Marinelli Luciana
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201803250
Subject(s) - metadynamics , peptidomimetic , rational design , pentapeptide repeat , chemistry , in vivo , integrin , docking (animal) , combinatorial chemistry , biophysics , stereochemistry , biochemistry , computational biology , receptor , nanotechnology , peptide , biology , molecular dynamics , medicine , materials science , computational chemistry , microbiology and biotechnology , nursing
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 of 6 for medical applications.