Squalene epoxidase (SQLE), also known as squalene monooxygenase, catalyzes the stereospecific conversion of squalene to 2,3( S )-oxidosqualene, a key step in cholesterol biosynthesis. SQLE inhibition is targeted for the treatment of hypercholesteremia, cancer, and fungal infections. However, lack of structure-function understanding has hindered further progression of its inhibitors. We have determined the first three-dimensional high-resolution crystal structures of human SQLE catalytic domain with small molecule inhibitors (2.3 Å and 2.5 Å). Comparison with its unliganded state (3.0 Å) reveals conformational rearrangements upon inhibitor binding, thus allowing deeper interpretation of known structure-activity relationships. We use the human SQLE structure to further understand the specificity of terbinafine, an approved agent targeting fungal SQLE, and to provide the structural insights into terbinafine-resistant mutants encountered in the clinic. Collectively, these findings elucidate the structural basis for the specificity of the epoxidation reaction catalyzed by SQLE and enable further rational development of next-generation inhibitors.

Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.

Dichloroacetate (DCA) decreases blood, cerebral spinal fluid, and intracellular lactate concentrations by activating the mitochondrial pyruvate dehydrogenase enzyme complex. The authors reviewed the efficacy of this investigational drug in the treatment of acquired or congenital forms of lactic acidosis from data in 40 English-language publications. The hypolactatemic effect of DCA occurs over a broad range of pretreatment lactate concentrations and is directly related to the baseline lactate level. The maximum lactate-lowering effect of the drug is dependent on its dose but independent of time following its administration. Recent clinical studies of acquired lactic acidosis suggest that DCA could be rapidly effective in reducing this risk factor of mortality in patients with mild hyperlactatemeia.

Dichloroacetate (DCA) decreases blood, cerebral spinal fluid, and intracellular lactate concentrations by activating the mitochondrial pyruvate dehydrogenase enzyme complex. The authors reviewed the efficacy of this investigational drug in the treatment of acquired or congenital forms of lactic acidosis from data in 40 English-language publications. The hypolactatemic effect of DCA occurs over a broad range of pretreatment lactate concentrations and is directly related to the baseline lactate level. The maximum lactate-lowering effect of the drug is dependent on its dose but independent of time following its administration. Recent clinical studies of acquired lactic acidosis suggest that DCA could be rapidly effective in reducing this risk factor of mortality in patients with mild hyperlactatemeia.

The pharmacokinetics of florfenicol were studied in koi carp Cyprinus carpio (hereafter, koi) and threespot gourami Trichogaster trichopterus after oral (50 mg/kg) and intramuscular (25 mg/kg) administration of the drug in warm water conditions (24-25ЊC). The estimates of clearance, volume of distribution, and half-life were 0.05 L · h Ϫ1 · kg Ϫ1 , 1.0 L/kg, and 16 h, respectively, in koi. In threespot gourami, the corresponding estimates were 0.32 L · h Ϫ1 · kg Ϫ1 , 2.0 L/kg, and 4 h. In koi, minimal drug absorption was observed after bath treatment. Analysis of florfenicol leaching from fish feed indicated that about 50-80% of the coated drug is lost and is not available for therapeutic benefit for either species. The minimum inhibitory concentrations of florfenicol, determined for bacterial isolates from tropical fish, ranged from 0.5 to 2 g/mL. For effective dosing regimens in koi and threespot gourami, the differences in pharmacokinetics should be considered in future studies.