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.

Identification of Human Alanine-Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1 / Grottelli, Silvia; Annunziato, Giannamaria; Pampalone, Gioena; Pieroni, Marco; Dindo, Mirco; Ferlenghi, Francesca; Costantino, Gabriele; Cellini, Barbara. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 65:14(2022), pp. 9718-9734. [10.1021/acs.jmedchem.2c00142]

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

Annunziato, Giannamaria
;
Pieroni, Marco;Ferlenghi, Francesca;Costantino, Gabriele;Cellini, Barbara
2022-01-01

Abstract

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.
2022
Identification of Human Alanine-Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1 / Grottelli, Silvia; Annunziato, Giannamaria; Pampalone, Gioena; Pieroni, Marco; Dindo, Mirco; Ferlenghi, Francesca; Costantino, Gabriele; Cellini, Barbara. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 65:14(2022), pp. 9718-9734. [10.1021/acs.jmedchem.2c00142]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2929374
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