Abstract 10013: PRDs Are Multifunctional Oral Inhibitors of PCSK9 and ACAT2

Introduction and Hypothesis: PCSK9-inhibition reduces the residual cardiovascular risk associated with LDL-cholesterol (LDL-C), but the wide-spread use of the antibody-based therapies is affected by the costs, especially in low- and middle-income countries. Hence, there is a need to identify affordable and effective drugs to inhibit PCSK9. Methods: Female and male C57BL/6J mice were fed a high fat diet prior to and during eight weeks of oral treatment with PRD125 (10 mpk/day), a molecule originally developed as a selective inhibitor of ACAT2. Also, HepG2 cells were incubated with PRD125 or PRD017 (1 and 10 μg/mL) in the presence or absence of atorvastatin (5 μmol/L). Results: PRD125 significantly reduced serum concentrations of LDL-C (-30% to -50%) and PCSK9 (>-60%), without significantly affecting PCSK9 mRNA levels. Additionally, significant decreases in fasting glucose (-17%) and HOMA-IR (-50%) were also observed. As the effects by PRD125 on serum concentrations of PCSK9 were posttranscriptional, we studied whether PRD125 or PRD017 may exert similar effects in human hepatocyte-like HepG2 cells. While atorvastatin significantly increased cellular PCSK9 protein levels (~40%), significant decreased levels (~40%) were observed by PRD125 or PRD017, regardless of the presence or absence of atorvastatin. Contrary to atorvastatin, and in line with the observation in mice, PRD125 and PRD017 did not affect PCSK9 mRNA levels. Conclusion: PRD125 and PRD017 are non-species-specific posttranscriptional inhibitors of PCSK9, that exert their functions in the presence or absence of cholesterol synthesis inhibition by atorvastatin. As PRD125 also improves glucose tolerance and decreases atherosclerosis in mice by inhibiting ACAT2, PRD125 can be considered as a progenitor of a new group of multifunctional orally active molecules with great potential for treatment and prevention of atherosclerosis and cardiometabolic diseases.