title: Tailoring of integrin ligands: probing the charge capability of the metal ion-dependent adhesion site.
abstract: Intervention in integrin-mediated cell adhesion and integrin signaling pathways is an ongoing area of research in medicinal chemistry and drug development. One key element in integrin-ligand interaction is the coordination of the bivalent cation at the metal ion-dependent adhesion site (MIDAS) by a carboxylic acid function, a consistent feature of all integrin ligands. With the exception of the recently discovered hydroxamic acids, all bioisosteric attempts to replace the carboxylic acid of integrin ligands failed. We report that phosphinates as well as monomethyl phosphonates represent excellent isosters, when introduced into integrin antagonists for the platelet integrin αIIbβ3. The novel inhibitors exhibit in vitro and ex vivo activities in the low nanomolar range. Steric and charge requirements of the MIDAS region were unraveled, thus paving the way for an in silico prediction of ligand activity and in turn the rational design of the next generation of integrin antagonists.
authors.affiliation: Institute for Advanced Study and Center of Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bollinger
authors.forename: Florian
authors.initials: F
authors.lastname: Manzenrieder
authors.forename: Roman
authors.initials: R
authors.lastname: Kolb
authors.forename: Alexander
authors.initials: A
authors.lastname: Bochen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Neubauer
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Georg
authors.initials: G
authors.lastname: Moessmer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Pell
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lindner
authors.forename: Joseph
authors.initials: J
authors.lastname: Fanous
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
mesh_terms: D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D055672:Static Electricity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D063065:Organophosphonates; D010721:Phosphinic Acids; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex