Discovery of BI-9787, a potent zwitterionic ketohexokinase inhibitor with oral bioavailability.

Fructose metabolism by ketohexokinase (KHK) is implicated in a variety of metabolic disorders. KHK inhibition is a potential therapeutic strategy for the treatment of diseases including diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. The first small-molecule KHK-inhibitors have entered clinical trials, but it remains unclear if systemic inhibition of KHK by small-molecules will eventually benefit patients.

mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes.

Background: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models.

Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design.

A molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of D-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and intestinal isoform KHK-C and the peripheral isoform KHK-A.

Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.

Amino acid homeostasis is critical for many cellular processes. It is well established that amino acids are compartmentalized using pH gradients generated between organelles and the cytoplasm; however, the dynamics of this partitioning has not been explored. Here we develop a highly sensitive pH reporter and find that the major amino acid storage compartment in Saccharomyces cerevisiae, the lysosome-like vacuole, alkalinizes before cell division and re-acidifies as cells divide.

Synthesis of 2'-modified N6-methyladenosine phosphoramidites and their incorporation into siRNA.

A synthesis of 2'-fluoro and 2'-methoxy N6-methyladenosine phosphoramidites and their successful incorporation into oligonucleotides is reported. 2'-fluoro and 2́-methoxy modifications of sugars in siRNAs are known to aid stability and N6-methylation modifies the potency of therapeutic silencing RNAs (siRNA). We demonstrate that a combination of those modifications incorporated into the antisense strand of siRNA leads to efficient knockdown of a target gene in cells.