Identification of Human Alanine–Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1

Primary hyperoxaluria type I (PH1) is a rare kidney disease
due
to the deficit of alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5′-phosphate-dependent
enzyme responsible for liver glyoxylate detoxification, which in turn
prevents oxalate formation and precipitation as kidney stones. Many
PH1-associated missense mutations cause AGT misfolding. Therefore,
the use of pharmacological chaperones (PCs), small molecules that
promote correct folding, represents a useful therapeutic option. To
identify ligands acting as PCs for AGT, we first performed a small
screening of commercially available compounds. We tested each molecule
by a dual approach aimed at defining the inhibition potency on purified
proteins and the chaperone activity in cells expressing a misfolded
variant associated with PH1. We then performed a chemical optimization
campaign and tested the resulting synthetic molecules using the same
approach. Overall, the results allowed us to identify a promising
hit compound for AGT and draw conclusions about the requirements for
optimal PC activity.