A team of researchers from the School of Life Sciences, University of Hyderabad comprising Prof. P. Reddanna, Dr. Kumar Reddy and Dr. Nooruddin Khan and from Dr. Reddy’s Institute of Life Sciences comprising Mr. Harshavardhan Bhuktar, Mr. Sharda Shukla and Prof. Manojit Pal have validated the 12R-LOX as the target for the development of anti-psoriasis drugs through a series of in vitro and in vivo experiments, including generation of 12R-LOX overexpressing transgenic mice and efficacy of 12R-LOX inhibitors.
Arachidonic acid, the most dominant polyunsaturated fatty acid in mammalian systems, is mainly oxygenated by Cyclooxygenase (COX) and Lipoxygenase (LOX) pathways. While COX pathway leads to the formation of prostaglandins (PGs) and thromboxanes, LOX pathway majorly produces leukotrienes (LTs). These compounds, collectively termed as eicosanoids, are potent biologically active molecules with a bewildering variety of actions on different processes. The uncontrolled production of these eicosanoids leads to the manifestation of various inflammatory diseases like arthritis, psoriasis, coronary heart diseases, allergy, asthma, certain forms of cancer and even Alzheimer’s disease. As a result, COX and LOX have become the natural targets for the development of drugs for a variety of inflammatory disorders. Lipoxygenases (LOX) represent a family of non-heme iron containing dioxygenases that catalyze the regioselective and stereo selective dioxygenation of fatty acid substrates containing one or more (Z,Z)-l,4-pentadiene moieties.
Prof. P. Reddanna Dr. Nooruddin Khan
A recognized feature of psoriasis and other proliferative dermatoses is the accumulation in the skin of the unusual arachidonic acid metabolite, 12R-hydroxyeicosatetraenoic acid (12R-HETE), a product of 12R-Lipoxygenase (12R-LOX). Microarray studies, in humans, reveal that 12R-LOX was pathologically over-expressed during the Psoriasis and other proliferative skin dermatoses. Deletion of 12R-LOX in mice results in impaired development of skin, which accounts for post-natal lethality. Conversely, overexpression of 12R-LOX has been implicated in Psoriasis, while deleterious mutations resulting in inactivation of 12R-LOX results in ichthyosis (skin disorder) characterized by disruption of cell-barrier functions. Thus, 12R-LOX forms a potential target for the development of proliferative skin disorders, including psoriasis.
A team of researchers from the School of Life Sciences, University of Hyderabad (Prof. P. Reddanna, Dr. Kumar Reddy and Dr. Nooruddin Khan) and from Dr. Reddy’s Institute of Life Sciences (Mr. Harshavardhan Bhuktar, Mr. Sharda Shukla and Prof. Manojit Pal) have validated the 12R-LOX as the target for the development of anti-psoriasis drugs through a series of in vitro and in vivo experiments, including generation of 12R-LOX overexpressing transgenic mice and efficacy of 12R-LOX inhibitors. The lead compounds showing efficacy in vitro on the target enzyme and in vivo on animal models have been granted Indian Patent No. 377565 || Title: HETEROCYCLIC COMPOUNDS AS LIPOXYGENASE INHIBITORS, date of grant: 22/9/2021). A PCT has also been filed for this invention (International Publication number WO 2020/255156 A1, 24 Dec 2020).
This invention is the outcome of a collaborative project between the two institutions funded jointly by the Department of Science and Technology (DST) and Dr Reddy’s Laboratories Ltd (DRL), for a project on “12-R-Lipoxygenase as Target for Discovery and Development of Drugs Against Psoriasis”.