Ki: 78 pM for rat liver squalene synthase

The zaragozic acids (ZAs), which is a family of fungal metabolites containing a novel 4,6,7-trihydroxy-2,8-dioxobicyclo[3.2.1]octane-3,4,5-tricarboxylic acid core, have been independently discovered by two separate groups via screening natural product sources to discover inhibitors of squalene synthase.

In vitro: Zaragozic acid A, as well as it two analogs Zaragozic acid B and C were discovered from an unidentified sterile fungal culture, Spororniella intermedia, and Leptodontium elatius, respectively. Zaragozic acid A, B and C were reported to be three potent competitive inhibitors of rat liver squalene synthase with Ki values of 78 pM, 29 pM, and 45 pM, respectively. In addition, Zaragozic acid A, B and C could also inhibite cholesterol synthesis in Hep G2 cells [1].

In vivo: In the mouse model, zaragozic acid A was found to be an inhibitor of acute hepatic cholesterol synthesis (50% inhibitory dose of 200 μg/kg). The in-vivo inhibition of squalene synthase was accompanied by an accumulation of label from [3Hjmevalonate into farnesyl diphosphate, farnesol, as well as organic acids. In summary, these data showed the zaragozic acids were a new class of therapeutic agents with potential for the hypercholesterolemia treatment [1].

Clinical trial: Up to now, zaragozic acid A is still in the preclinical development stage.

Reference:
[1] Bergstrom JD,Kurtz MM,Rew DJ,Amend AM,Karkas JD,Bostedor RG,Bansal VS,Dufresne C,VanMiddlesworth FL,Hensens OD, et al.  Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc Natl Acad Sci U S A.1993 Jan 1;90(1):80-4.