title: Rational improvement of the affinity and selectivity of integrin binding of grafted lasso peptides.
abstract: Integrins moderate diverse important functions in the human body and are promising targets in cancer therapy. Hence, the selective inhibition of specific integrins is of great medicinal interest. Here, we report the optimization of a grafted lasso peptide, yielding MccJ25(RGDF), which is a highly potent and selective αvβ3 integrin inhibitor. Furthermore, its NMR structure was elucidated and employed in a molecular dynamics approach, revealing information about the integrin binding mode and selectivity profile of MccJ25(RGDF).
authors.affiliation: Department of Chemistry/Biochemistry, LOEWE Center for Synthetic Microbiology, Philipps-Universität Marburg , Hans-Meerwein-Strasse 4, 35032 Marburg, Germany.
authors.forename: Julian D
authors.initials: JD
authors.lastname: Hegemann
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: De Simone
authors.forename: Marcel
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Knappe
authors.forename: Xiulan
authors.initials: X
authors.lastname: Xie
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Marahiel
mesh_terms: D001430:Bacteriocins / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D012910:Snake Venoms / Q000494:pharmacology
chemical_list: D001430:Bacteriocins; D039302:Integrin alphaVbeta3; D010455:Peptides; D012910:Snake Venoms; C020411:microcin; C422910:Cilengitide