Acetyl-CoA carboxylase (ACC) is a biotin carboxylase that catalyzes the ATP-dependent condensation of acetyl-CoA and carbonate to form malonyl-CoA. The malonyl-CoA is an essential and rate-limiting substrate for de novo lipogenesis (DNL), and it acts as an allosteric inhibitor of the enzyme carnitine-palmitoyl transferase I (CPT-1)[1]. PF-05175157 is broad spectrum acetyl-CoA carboxylase (ACC) inhibitor with IC50 values of 27.0, 33.0, 23.5 and 50.4 nM for ACC1 (human), ACC2 (human), ACC1 (rat), ACC2 (rat), respectively[2]. In the First-in-Human study, single ascending doses of PF-05175157 ranging from 10 to 800 mg were safe and well-tolerated. Fructose stimulated DNL was inhibited over this time course; peak fructose-stimulated fractional DNL was reduced by 63.6% (90% CI = 75.1–52.0%) relative to placebo treatment[2]. PF-05175157 shows antiviral activities against West Nile virus (WNV) dengue virus (DENV) and Zika virus (ZIKV) with EC50 values of 2.7 ± 1.3 µM, 1.0 ± 0.3 µM and < 1.2 µM, respectively[3]. Murine model of WNV infection were treated with PF-05175157 (20 mg/kg) or drug vehicle twice a day p.o.. When compared to control animals, mice treated with PF-05175157 exhibited a significant decrease of viral load in plasma at 3 and 4 days after infection, a significant reduction in the amount of viral RNA in the kidney and a tendency for a reduction in the amount of viral RNA in the lung[3].
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