Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC50 = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

Data Fitting and Scenario Analysis of Vaccination in the 2014 Ebola Outbreak in Liberia

OBJECTIVES: This study aimed to extend an epidemiological model (SEIHFR) to analyze epidemic trends, and evaluate intervention efficacy. METHODS: SEIHFR was modified to examine disease transmission dynamics after vaccination for the Ebola outbreak. Using existing data from Liberia, sensitivity analysis of various epidemic scenarios was used to inform the model structure, estimate the basic reproduction number ℜ₀ and investigate how the vaccination could effectively change the course of the epidemic. RESULTS: If a randomized mass vaccination strategy was adopted, vaccines would be administered prophylactically or as early as possible (depending on the availability of vaccines). An effective vaccination rate threshold for Liberia was estimated as 48.74% among susceptible individuals. If a ring vaccination strategy was adopted to control the spread of the Ebola virus, vaccines would be given to reduce the transmission rate improving the tracing rate of the contact persons of an infected individual. CONCLUSION: The extended SEIHFR model predicted the total number of infected cases, number of deaths, number of recoveries, and duration of outbreaks among others with different levels of interventions such as vaccination rate. This model may be used to better understand the spread of Ebola and develop strategies that may achieve a disease-free state.