title: Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma.
abstract: The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and is a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma components might significantly compromise ligand efficacy. Surprisingly the binding strength between a particular ligand and TTR does not correlate well with its selectivity in plasma. However, through analysis of the thermodynamic signature using isothermal titration calorimetry we discovered a better correlation between selectivity and the enthalpic component of the interaction. This is of specific interest in the quest for more efficient TTR stabilizers, but a high selectivity is an almost universally desired feature within drug design and the finding might have wide-ranging implications for drug design.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Iakovleva
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Brännström
authors.affiliation: Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Department of Pharmacology and Clinical Neurosciences, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gharibyan
authors.affiliation: Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Afshan
authors.initials: A
authors.lastname: Begum
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Intissar
authors.initials: I
authors.lastname: Anan
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Walfridsson
authors.affiliation: Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.
authors.forename: A Elisabeth
authors.initials: AE
authors.lastname: Sauer-Eriksson
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University , 901 87 Umeå, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Olofsson
mesh_terms: D000686:Amyloidosis / Q000188:drug therapy; D002151:Calorimetry; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010949:Plasma / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry*; D011485:Protein Binding; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D008024:Ligands; D011228:Prealbumin