Endocrine Abstracts

The iodothyronine deiodinases constitute a family of three selenoenzymes regulating the intracellular metabolism of Thyroid Hormones (THs, T4 and T3) and impacting on several physiological processes, including energy metabolism, development and cell differentiation. The type 1, 2 and 3 deiodinases (D1, D2, and D3), are sensitive, rate-limiting components within the TH axis, and rapidly control TH action in physiological conditions or disease. Notably, several human pathologies are characterized by deiodinases deregulation (e.g., inflammation, osteoporosis, metabolic syndrome, muscle wasting and cancer). Consequently, these enzymes are golden targets for identifying and developing pharmacological compounds endowed with modulatory activities. However, until now, the portfolio of inhibitors for deiodinases is limited and the few active compounds lack selectivity. Screening a collection of FDA-approved drugs against an in silico model of murine D2, we identified a list of molecules with the potential ability to interact with D2. Among them, we validated the cephalosporin Cefuroxime as a novel D2 specific inhibitor. Using isotopes for deiodination activity determination, we demonstrated that Cefuroxime has the remarkable ability to inhibit D2 enzymatic activity without perturbing D1 and D3 function. Interestingly, acting as a specific D2 inhibitor, Cefuroxime has anti-thyroidal action in vivo. Indeed, it blocks D2 activity in the D2-expressing tissues, as the brown adipose tissue, the skeletal muscle and the anterior pituitary. Notably, in our experimental settings, Cefuroxime inhibits the enzymatic activity of D2 without altering the systemic TH status when administered in vivo in euthyroid mice for 15 days. However, despite we show for Cefuroxime a very interesting inhibitory activity, highly specific for D2, its eligibility as negative modulator of D2 in human is unlikely, mainly as a consequence of its antibiotic activity, (long term toxicity, negative effect on human microbiota, risk of selection of Cefuroxime resistant bacteria). Notwithstanding, we think that the identification of a synthetic ligand endowed with specificity for D2 will allow the beginning of a drug optimization process toward the development of new hits that will maintain selectivity toward D2, while losing their antibiotic potential. In conclusion, these data prove a novel activity of the antibacterial drug Cefuroxime and demonstrate that this compound can be viewed as a potent modulator of the peripheral conversion of T4-to-T3, preventing the local amplification of the TH signal in pathophysiological conditions.