Fe(II) with Tris(1-pyrazolyl)methane Complex Increases Thermal Stability In Vitro and Activity In Vivo of the Mutant...

Pharmacological chaperones (PCs)-small molecules that normalize the 3D structure of mutant protein molecules-are promising substances for pharmacological treatment of grave hereditary pathologies. In this study, possible chaperone-like effects of the Fe(II) with tris(1-pyrasolyl)methane complex, [Fe(TPM)₂]Cl₂, on the mutant 447R form of mouse tryptophan hydroxylase 2 (TPH2) in vitro and in vivo were investigated. The experiments were carried out on Balb/c mice homozygous for the mutant TPH2. This complex in concentrations of 0.01, 0.05 and 0.1 mM markedly increased the temperature (T₅₀) and free energy (ΔG) of the mutant TPH2 thermal denaturation in vitro. Seven intramuscular administrations of 30 and 60 mg/kg of [Fe(TPM)₂]Cl₂ markedly increased the TPH2 activity in the midbrain of Balb/c mice. This increase in the TPH2 activity was not accompanied with an increase in the Tph2 gene mRNA and TPH2 protein levels. It is the first demonstration of chaperone-like activity of [Fe(TPM)₂]Cl₂. This complex is a promising chemical for correction of genetic alterations in TPH2 and the associated hereditary psychic disorders.