Development of PDE inhibitors to treat neglected parasitic diseases

Five academic institutions, two governmental institutes and two leading SMEs from Europe, Africa and Latin America are joining forces to develop novel drugs against parasites. The 4-year EU-funded project led by the Division of Medicinal Chemistry of VU University Amsterdam is called PDE4NPD: PhosphoDiEsterase inhibitors for Neglected Parasitic Diseases.

Standstill in neglected disease treatment
Neglected parasitic diseases (NPDs) form an enormous obstacle to the development of communities across the world. The diseases are classified ‘neglected’ as investments in finding cures for these illnesses are extremely low, especially when considering their devastating impact on human and veterinary health. The NPDs addressed in this project – Chagas’ disease, human African trypanosomiasis, leishmaniasis and schistosomiasis – collectively result in 6.6 million disability-adjusted life years.

During the last 30 years, only 9 new drugs targeting these NPDs have come to market. Some of these treatments cause severe side effects, while others are very expensive or are threatened by drug resistance. A cause for this standstill is the lack of sufficient financial incentive, due to the low return on investment perspective for the pharmaceutical industry. A paradigm shift in policy and a substantial joint effort to address this drug discovery gap is urgently required.

Drug discovery platform
The PDE4NPD project enables public and private partners to join forces within the EU Seventh Framework program to tackle these healthcare needs. The consortium consists of VU University Amsterdam (NL), University of Glasgow (UK), University of Kent (UK), University of Antwerp (BE), The Spanish National Research Council (ES), Fundação Oswaldo Cruz (BR), Theodor Bilharz Research Institute (EG), European Screening Port (DE), IOTA Pharmaceuticals (UK) and Top Institute Pharma (NL) and combines various drug discovery approaches into one platform that is dedicated to developing drugs against parasite PDEs: a family of well characterized enzymes.

“Previous studies have shown that PDEs are highly druggable and that targeting parasite PDEs is a viable strategy to combat these diseases”, states principal investigator Rob Leurs of VU University, as well-known drugs such as Viagra® and Daxas® effectively target illnesses caused by human PDEs. He continues: “This consortium has all the expertise to develop parasite‐specific PDE inhibitors with high clinical potential. We will use state-of-the-art structural biology and screening technologies for finding new molecules with drug-like properties.”

In parallel, the consortium parasitology research groups will perform phenotypic screening on various parasite species to identify agents that will kill them. The consortium will further develop compounds demonstrating anti-parasitic activity through PDEs as the key drug target. Leurs: “Ultimately, PDE4NPD will develop into a generic platform in which any parasite PDE can be enrolled. The integrative approach allows the accumulation of fundamental knowledge with an efficiency that is typical for approaches that focus on a single cellular target.”

Role of the Division of Medicinal Chemistry
Next to the overall coordination of the consortium, the research teams of Rob Leurs and Iwan de Esch will use their experience and skills in early drug discovery to find and develop new drug molecules against parasitic PDEs. Their research is also embedded in the Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), which focuses on the elucidation of molecular mechanisms of diseases and the development of novel and safer drugs, therapeutics and diagnostics.

PDE-inhibitors

Prof. De Esch explains: “Our expertise in computational and synthetic chemistry is a perfect match with this project. We also use a method called fragment-based drug discovery. First, we identify small chemical fragments that bind to different parts of the PDE. We then combine these fragments to a larger compound with higher affinity for the target. Hence, with insights in PDE protein structures that other partners obtain, we will design and synthesize perfect fits for the parasitic PDEs without hitting the human counterparts.”