Curtis W. Pazderka, Brian Oliver, Michael Murray and Tristan Rawling* Pages 1670 - 1689 ( 20 )
Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play crucial and often opposing regulatory roles in health and in pathological conditions. n-3 and n-6 PUFA undergo biotransformation to parallel series of lipid mediators that are potent modulators of many cellular processes. A wide range of biological actions have been attributed to lipid mediators derived from n-6 PUFA, and these mediators have served as lead compounds in the development of numerous clinically approved drugs, including latanoprost (Xalatan: Pfizer), which is listed on the WHO Model List of Essential Medicines. n-3 PUFA-derived mediators have received less attention, in part because early studies suggested that n-3 PUFA act simply as competitive substrates for biotransformation enzymes and decrease the formation of n-6 PUFA-derived lipid mediators. However, more recent studies suggest that n-3 PUFA-derived mediators are biologically important in their own right. It is now emerging that many n-3 PUFA-derived lipid mediators have potent and diverse activities that are distinct from their n-6 counterparts. These findings provide new opportunities for drug discovery. Herein, we review the biosynthesis of n-3 PUFA-derived lipid mediators and highlight their biological actions that may be exploited for drug development. Lastly, we provide examples of medicinal chemistry research that has utilized n-3 PUFA-derived lipid mediators as novel lead compounds in drug design.
Polyunsaturated fatty acids, lipid mediators, oxylipin, omega-3, biotransformation, drug design strategies.
School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo NSW 2007, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo NSW 2007, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney NSW 2006, School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo NSW 2007