The metabolism of polyunsaturated fatty acids (PUFAs) leads to the formation of a wide variety of lipid mediators such as prostaglandins, thromboxanes, leukotrienes and lipoxins. These local hormones, generally termed “eicosanoids”, regulate many important biological processes such as maintenance of homeostasis, blood pressure, renal function, reproduction as well as the immune system. Under pathophysiological conditions they are responsible for pain, fever, and inflammation. As such, enzymes involved in PUFA metabolism are among the most important drug targets. Two examples are cyclooxygenases, the targets of non-steroidal anti-inflammatory drugs such as aspirin, aetaminophen and ibuprophen, and lipoxygenases, targets for which few drugs have been developed. A complicating factor in the development of lipoxygenase inhibitors is that there are 6 isoforms of the enzyme in humans, all of which have different functions, necessitating that the inhibitor be selective for one isoform over the others. 

 

Our group is working towards selective inhibitors for lipoxygenases, both as potential drug leads and to provide further structural and mechanistic information on the various isoforms of human lipoxygenases.

 

Two projects ongoing in our laboratories:

 

Cyclopropanated and fluorinated polyunsaturated fatty acids as substrate analogs for lipoxygenases

 

Acetaminophen-inspired, but mechanistically distinct, inhibitors of lipoxygenases