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Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.

ABSTRACT: Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays-a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ-bezafibrate, PPARγ-fenofibric acid, and PPARδ/γ-pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.

SUBMITTER: Honda A

PROVIDER: S-EPMC9102038 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.

Honda Akihiro A Kamata Shotaro S Akahane Makoto M Machida Yui Y Uchii Kie K Shiiyama Yui Y Habu Yuki Y Miyawaki Saeka S Kaneko Chihiro C Oyama Takuji T Ishii Isao I

International journal of molecular sciences 20220425 9

Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPAR ...[more]

PMID: 35563117

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Project description:BackgroundPPARα and cyclooxygenase (COX)-2 are overexpressed in certain types of cancer. Thus, developing a dual inhibitor that targets both could be more effective as an anticancer agent than single inhibitors. We have previously shown that an analog of the bezafibrate named AA520 is a PPARα antagonist. Herein, we report the identification of AA520 as a potent COX-2 inhibitor using in silico approaches. In addition, we performed a thorough pharmacological characterization of AA520 towards COX-1 and COX-2 in different in vitro models.MethodsAA520 was characterized for inhibiting platelet COX-1 and monocyte COX-2 activity in human whole blood (HWB) and for effects on lipidomics of eicosanoids using LC-MS/MS. The kinetics of the interaction of AA520 with COX-2 was assessed in the human colon cancer cell line, HCA-7, expressing only COX-2, by testing the COX-2 activity after extensive washing of the cells. The impact of AA520 on cancer cell viability, metabolic activity, and cytotoxicity was tested using the MTT reagent.ResultsIn HWB, AA520 inhibited in a concentration-dependent fashion LPS-stimulated leukocyte prostaglandin (PG) E2 generation with an IC50 of 0.10 (95% CI: 0.05-0.263) μM while platelet COX-1 was not affected up to 300 μM. AA520 did not affect LPS-induced monocyte COX-2 expression, and other eicosanoids generated by enzymatic and nonenzymatic pathways. AA520 inhibited COX-2-dependent PGE2 generation in the colon cancer cell line HCA7. Comparison of the inhibition of COX-2 and its reversibility by AA520, indomethacin (a time-dependent inhibitor), acetylsalicylic acid (ASA) (an irreversible inhibitor), and ibuprofen (a reversible inhibitor) showed that the compound is acting by forming a tightly bound COX-2 interaction. This was confirmed by docking and molecular dynamics studies. Moreover, AA520 (1 μM) significantly reduced MTT in HCA7 cells.ConclusionWe have identified a highly selective COX-2 inhibitor with a unique scaffold. This inhibitor retains PPARα antagonism at the same concentration range. It has the potential to be effective in treating certain types of cancer, such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), where COX-2 and PPARα are overexpressed.

Project description:Statins, the intestinal cholesterol transporter inhibitor (ezetimibe), and PCSK9 inhibitors can reduce serum LDL-C levels, leading to a significant reduction in cardiovascular events. However, these events cannot be fully prevented even when maintaining very low LDL-C levels. Hypertriglyceridemia and reduced HDL-C are known as residual risk factors for ASCVD. Hypertriglyceridemia and/or low HDL-C can be treated with fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids. Fibrates were demonstrated to be PPARα agonists and can markedly lower serum TG levels, yet were reported to cause some adverse effects, including an increase in the liver enzyme and creatinine levels. Recent megatrials of fibrates have shown negative findings on the prevention of ASCVD, which were supposed to be due to their low selectivity and potency for binding to PPAR α. To overcome the off-target effects of fibrates, the concept of a selective PPARα modulator (SPPARMα) was proposed. Kowa Company, Ltd. (Tokyo, Japan), has developed pemafibrate (K-877). Compared with fenofibrate, pemafibrate showed more favorable effects on the reduction of TG and an increase in HDL-C. Fibrates worsened liver and kidney function test values, although pemafibrate showed a favorable effect on liver function test values and little effect on serum creatinine levels and eGFR. Minimal drug-drug interactions of pemafibrate with statins were observed. While most of the fibrates are mainly excreted from the kidney, pemafibrate is metabolized in the liver and excreted into the bile. It can be used safely even in patients with CKD, without a significant increase in blood concentration. In the megatrial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL-C and LDL-C levels, the incidence of cardiovascular events did not decrease among those receiving pemafibrate compared to those receiving the placebo; however, the incidence of nonalcoholic fatty liver disease was lower. Pemafibrate may be superior to conventional fibrates and applicable to CKD patients. This current review summarizes the recent findings on pemafibrate.

Project description:Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-cholesterol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates' clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for better efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyceride reduction and HDL-C elevation.Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creatinine or decrease the estimated glomerular filtration rate. There were extremely few drug interactions even when it was used concomitantly with various statins. Furthermore, unlike many of the conventional fibrates that are renal excretory-type drugs, pemafibrate is excreted into the bile, so it can be safely used even in patients with impaired renal function and there is no increase in its blood concentration.This novel SPPARMα, pemafibrate, has superior benefit-risk balance compared to conventional fibrates and can be used for patients for whom it was difficult to use existing fibrates, including those who are taking statins and those with renal dysfunction. A large-scale trial PROMINENT using pemafibrate for patients with type 2 diabetes is in progress. In the current review, the latest data on pemafibrate will be summarized.

Dataset Information

Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.

Publications

Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.

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