title: Drug screening boosted by hyperpolarized long-lived states in NMR.
abstract: Transverse and longitudinal relaxation times (T1ρ and T1) have been widely exploited in NMR to probe the binding of ligands and putative drugs to target proteins. We have shown recently that long-lived states (LLS) can be more sensitive to ligand binding. LLS can be excited if the ligand comprises at least two coupled spins. Herein we broaden the scope of ligand screening by LLS to arbitrary ligands by covalent attachment of a functional group, which comprises a pair of coupled protons that are isolated from neighboring magnetic nuclei. The resulting functionalized ligands have longitudinal relaxation times T1((1)H) that are sufficiently long to allow the powerful combination of LLS with dissolution dynamic nuclear polarization (D-DNP). Hyperpolarized weak "spy ligands" can be displaced by high-affinity competitors. Hyperpolarized LLS allow one to decrease both protein and ligand concentrations to micromolar levels and to significantly increase sample throughput.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne (Switzerland).
authors.forename: Roberto
authors.initials: R
authors.lastname: Buratto
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bornet
authors.forename: Jonas
authors.initials: J
authors.lastname: Milani
authors.forename: Daniele
authors.initials: D
authors.lastname: Mammoli
authors.forename: Basile
authors.initials: B
authors.lastname: Vuichoud
authors.forename: Nicola
authors.initials: N
authors.lastname: Salvi
authors.forename: Maninder
authors.initials: M
authors.lastname: Singh
authors.forename: Aurélien
authors.initials: A
authors.lastname: Laguerre
authors.forename: Solène
authors.initials: S
authors.lastname: Passemard
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gerber-Lemaire
authors.forename: Sami
authors.initials: S
authors.lastname: Jannin
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bodenhausen
mesh_terms: D001965:Bromides / Q000737:chemistry; D020134:Catalytic Domain; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry
chemical_list: D001965:Bromides; D008024:Ligands; D011506:Proteins; D013876:Thiophenes
keywords: NMR spectroscopy; drug discovery; dynamic nuclear polarization; long-lived states