Academic brain and industrial muscle came together to make DHODH an award winning drug discovery project.
His Excellency President Kikwete of Tanzania presented the coveted MMV Project of the Year 2010 award to Prof. Meg Phillips and her collaborators on the first day of the MMV Stakeholders’ Meeting. The award was presented in recognition of the international team’s impressive progress to rapidly bring DHODH inhibitors towards clinical testing.
Dihydroorotate dehydrogenase (DHODH) is one the hottest malaria drug targets under investigation today. The University of Texas Southwestern’s project, led by Prof. Meg Phillips, set out to discover and develop targeted inhibitors able to hit this enzyme and stop the parasite in its tracks.
From the very outset, scientists at the University of Texas Southwestern 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 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 of Texas Southwestern’s compound library and later identified by chemists as molecules with great antimalarial potential.
Select molecules from the series are now undergoing preclinical tests to identify which candidate should move forward. The results are promising and suggest 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.
“Understanding the Plasmodium DHODH has been a difficult process. The challenges faced at every turn while researching this enzyme over the last 5 years have made it a really intellectually stimulating project.” Dr Ian Bathurst, MMV Project Director.
“In the future I hope that we see a compound out there in the clinic treating people – that would be the coolest thing that could happen in my entire career.” Prof. Meg Phillips, University of Texas Southwestern.
“We wish to commend this group of dedicated scientists led by Prof. Phillips for joining forces to develop a new and innovative medicine for malaria.” Dr David Reddy, CEO, MMV
Pictured above: David Reddy, Jeff Klinger, Jose Coteron, President Kikwete of Tanzania, Sue Charman, Meg Phillips, Pradip Rathod, Baroness Chalker, Ray Chambers
Core DHODH Team:
Prof Meg Phillips, University of Texas Southwestern Medical Centre and project leader, responsible for enzymology and structural biology
Prof. Pradip Rathod, University Washington, responsible for chemistry and parasitology
Prof. Susan Charman, Monash University, responsible for pharmacokinetics, drug metabolism and physicochemistry
Significant input from the team at GSK Tres Cantos for medicinal chemistry (Jose Coteron) and in vivo efficacy; and information sharing with Genzyme (Jeff Klinger)
MMV advisors: Ian Bathurst, Jeremy Burrows and several other scientific advisors
NIH: John Rogers program officer