Characteristics of pyripyropene fungal alkaloids and synthetic derivatives targeting ACAT2 as insecticides, anti-atherosclerosis and anticancer agents.

The pyripyropenes A-X represent a family of 24 alkaloids isolated from fungi, mainly Aspergillus and Penicillium species, over the past 30 years. Numerous analogues have been isolated from fungi or (hemi)synthesized to investigate structure-activity relationships. The leader product in the series remains the first identified natural product pyripyropene A (Pyri-A), known as a highly potent and selective inhibitor of acyl CoA:cholesterol acyltransferase 2 (ACAT2). The present review retraces the products history, from their discovery to the characterization of the target engagement, the cellular mechanism of action and bioactivities. In parallel to the identification of naturally occurring pyripyropenes and the synthesis of derivatives, studies have progressed in three directions. First, the development of agricultural insecticides from Pyri-A led to discovery and worldwide commercialization of afidopyropen (Inscalis®) to protect crops against sucking insects. Second, the highly potent and selective targeting of ACAT2, largely expressed in human liver cells notably, drove the design of analogues aimed at regulating cholesterol metabolism for the treatment of metabolic and cardiovascular diseases. Third, the emerging roles of ACAT2 as a regulator of tumor cell proliferation and anticancer immune response call for the development of the pyripyropenes in oncology. A few tumor-active pyripyropene derivatives targeting ACAT2 have been identified recently. The review underlines the evolution of research in this domain, from the fungal production to the insecticidal action, and from the treatment of atherosclerosis to cancers. The pyripyropene saga is alive and well.