Drug Screening Boosted by Hyperpolarized Long-Lived States in NMR.

Roberto Buratto , Aurélien Bornet , Jonas Milani , Daniele Mammoli , Basile Vuichoud , Nicola Salvi , Maninder Singh , Aurélien Laguerre , Solène Passemard (1) , Sandrine Gerber-Lemaire (1) , Sami Jannin (2) , Geoffrey Bodenhausen (3)

1 EPFL - Ecole Polytechnique Fédérale de Lausanne
2 ISIC - Institut des sciences et d'ingénierie chimiques
3 UPMC - Université Pierre et Marie Curie - Paris 6

: 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.

Domaines: Chimie organique

Roberto Buratto, Aurélien Bornet, Jonas Milani, Daniele Mammoli, Basile Vuichoud, et al.. Drug Screening Boosted by Hyperpolarized Long-Lived States in NMR.. ChemMedChem, 2014, 9 (11), pp.2509-2515. ⟨10.1002/cmdc.201402214⟩. ⟨hal-01064612⟩