The enzyme dihydroorotate dehydrogenase (DHODH) is one the hottest malaria drug targets under investigation today. The University of Texas Southwestern’s project to discover and develop targeted inhibitors with the ability to hit this target and stop the parasite in its tracks was awarded MMV’s 2010 Project of the Year in recognition of its impressive progress to rapidly bring these inhibitors towards clinical testing.
From the very outset, scientists at the University knew they had found something special in DHODH. Unlike other species, including humans, Plasmodium species are completely reliant on this enzyme for survival. Additionally, due to biological differences between the parasite and man, with respect to the enzyme, scientists can be confident that a medicine targeted at Plasmodium’s DHODH will not have the same effect in humans.
A series of molecules known as the triazolopyrimidines were identified via a high throughput screen of the University compound library and later identified by chemists as molecules with great potential.
Select molecules from the series are now undergoing preclinical tests to identify which candidate should move forward. The results are promising and suggest that the molecules are long lasting and active against the blood-stage of P. falciparum. Based on this we already know that, if successful, the final medicine could be delivered as a once-a-day dose. If all goes according to plan we could hope to see a DHODH inhibitor available and saving the lives of people suffering from malaria in the next 5-6 years.
→ Go to an interview with Dr Meg Phillips, University of Texas Southwestern, USA
→ Got to an interview with Dr Ian Bathurst.