The overall aim of this proposal is to understand the fibrate mechanism of action in diabetes and its complications. Our studies demonstrate that 1) fenofibrate is most potent among all the fibrates tested in inhibiting aldose reductase (AR) activity in vitro; 2) fenofibric acid shows less potency in inhibiting AR catalyzed forward reaction and only in the pH range 5.0- 6.0 unlike fenofibrate; and 3) first structure and binding proof affirms that AR is a drug target for fibrate derivative, WY 14,643. Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to its active metabolite, fenofibric acid. Unchanged fenofibrate (prodrug) has been reported to be undetectable in plasma samples following an oral dose. Fibrates are successful in the treatment of hypertriglyceridaemia or mixed hyperlipidaemia. On the other hand AR is known to play a significant role in diabetes and its complications and numerous attempts to identify inhibitors for the treatment of AR mediated complications have not proven successful. Exposure to high levels of glucose induces the production of reactive oxygen species (ROS) which may modify AR by oxidizing Cys residues to sulfenic acids and the sulfenic acid modified AR shows higher enzyme activity. The objective of this proposal is to evaluate the role of fibrate derivatives in the function of wild-type and C298X mutant AR.
The SPECIFIC AIMS are 1) determine the inhibition potency and molecular interactions of fenofibrate derivatives; 2) establish the role of Cys298 in AR enzyme activity in the presence of newly synthesized fenofibrate derivatives, and 3) evaluate the function of the Cys298 modified AR in the presence of fibrate derivatives. The project will combine chemical, biochemical (spectrofluorometric enzymatic assays) and molecular (structural methods) approaches with the use of recombinant and cell culture samples. We expect that the results obtained from these studies will further our understanding of the nature of fibrate mechanism under normal and high glucose conditions.
Approximately 347 million people were estimated to have diabetes worldwide in 2008, an increase of 194 million cases from 1980. By the year 2025, there will be more than 300 million type 2 diabetes sufferers worldwide. According to 2016 CDC report more than 29 million Americans are living with diabetes, and 86 million are living with prediabetes, a serious health condition that increases a individual's risk of type 2 diabetes and other chronic diseases. Antilipidemic drugs reduce the incidence of delayed onset of diabetes in patients with impaired fasting glucose. Our findings suggest that these drugs are better inhibitors for an enzyme that converts excess glucose to sorbitol under diabetic condition and plan to study their mechanism in diabetes and its complications.
| Kotheimer, Amanda E; Haq, Wahajul; Balendiran, Ganesaratnam K (2018) Synthesis and Chiral Separation of Fibratol, Isopropyl 2-(4-((4-chlorophenyl)(hydroxyl) methyl)-phenoxy)-2-methylpropanoate. Int J Org Chem (Irvine) 8:201-206 |
| Sawaya, Michael R; Verma, Malkhey; Balendiran, Vaishnavi et al. (2016) Characterization of WY 14,643 and its Complex with Aldose Reductase. Sci Rep 6:34394 |
| Balendiran, Ganesaratnam K; Pandian, J Rajendran; Drake, Evin et al. (2014) B-factor Analysis and Conformational Rearrangement of Aldose Reductase. Curr Proteomics 11:151-160 |
| Balendiran, Ganesaratnam K; Rath, Niharika; Kotheimer, Amanda et al. (2012) Biomolecular chemistry of isopropyl fibrates. J Pharm Sci 101:1555-69 |
| Balendiran, Ganesaratnam K; Sawaya, Michael R; Schwarz, Frederick P et al. (2011) The role of Cys-298 in aldose reductase function. J Biol Chem 286:6336-44 |
| Balendiran, Ganesaratnam K (2009) Fibrates in the chemical action of daunorubicin. Curr Cancer Drug Targets 9:366-9 |
| Balendiran, Ganesaratnam K; Martin, Hans-Joerg; El-Hawari, Yasser et al. (2009) Cancer biomarker AKR1B10 and carbonyl metabolism. Chem Biol Interact 178:134-7 |
