squalestatin-1 and Aspergillosis

Invasive aspergillosis (IA) is a life-threatening disease impacting immunocompromised individuals. Standard treatments of IA, including polyenes and azoles, suffer from high toxicity and emerging resistance, leading to the need to develop new antifungal agents with novel mechanisms of action. Ergosterol biosynthesis is a classic target for antifungals, and squalene synthase (SQS) catalyzes the first committed step in ergosterol biosynthesis in Aspergillus spp. making SQS of interest in the context of antifungal development. Here, we cloned, expressed, purified and characterized SQS from the pathogen Aspergillus flavus (AfSQS), confirming that it produced squalene. To identify potential leads targeting AfSQS, we tested known squalene synthase inhibitors, zaragozic acid and the phosphonosulfonate BPH-652, finding that they were potent inhibitors. We then screened a library of 744 compounds from the National Cancer Institute (NCI) Diversity Set V for inhibition activity. 20 hits were identified and IC

Topics: Antifungal Agents; Aspergillosis; Aspergillus flavus; Bridged Bicyclo Compounds, Heterocyclic; Cloning, Molecular; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Humans; Models, Molecular; Molecular Targeted Therapy; Pentacyclic Triterpenes; Tricarboxylic Acids; Triterpenes