Development of potent non-acylhydrazone inhibitors of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b).

Inhibition of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b), responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Previously, we aimed to identify new drugs for hyperphosphatemia treatment and obtained zwitterionic compound 3 (IC = 64 nM) as a potent selective inhibitor of intestinal NaPi2b. This small-molecule compound is gut-restricted owing to its almost membrane-impermeable property.

Discovery of Gut-Restricted Small-Molecule Inhibitors of Intestinal Sodium-Dependent Phosphate Transport Protein 2b (NaPi2b) for the Treatment of Hyperphosphatemia.

NaPi2b is primarily expressed in the small intestine, lungs, and testes and plays an important role in phosphate homeostasis. The inhibition of NaPi2b, responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Using a novel phosphate uptake inhibitor (IC = 87 nM), identified from an in-house compound collection in human NaPi2b-transfected cells as a prototype compound, we conducted its derivatization based on a Ro5-deviated strategy to develop orally administrable small-molecule NaPi2b inhibitors with nonsystemic exposure.

Direct binding of ligandin to uridine 5'-diphosphate glucuronosyltransferase 1A1.

Aim: Bilirubin, a final degradation product of heme produced mainly in the spleen, is carried to the liver through its binding to albumin in the blood circulation. After its transport to hepatocytes, ligandin (glutathione S-transferase; GST) carries bilirubin to the endoplasmic reticulum (ER). uridine 5'-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin for solubilization in the ER.

UDP-glucuronosyltransferase1A1 directly binds to albumin.

UDP-glucuronosyltransferase1A1 (UGT1A1) catalyses glucuronidation of bilirubin (the final break down product of heme which is produced mainly in the spleen and liver) and is located on the lumen of the endoplasmic reticulum (ER). To identify partner UGTs that form hetero-oligomers with UGT1A1, or other proteins that bind directly to UGT1A1, yeast two-hybrid screening was performed using UGT1A1 as bait. From these studies, cDNA clones specific for human serum albumin (HSA) were unexpectedly isolated.