|Jointly Changing the Future for Human African Sleeping Sickness – PDE Inhibitors asTrypanocidals
K M Orrling1, C Jansen1, A Shanmugham1, T Seebeck2, H Tenor3, G J Sterk4, I de Esch1, R Leurs11Leiden/Amsterdam Centre of Drug Research (LACDR), Division of Medicinal Chemistry, VU University Amsterdam, The Netherlands, 2Institute of Cell Biology, University of Bern, Switzerland,3Nycomed, Konstanz, Germany, 4Mercachem, Nijmegen, The Netherlands. E-mail: K.M.Orrling@vu.nl
Drug discovery is a highly interdisciplinary matter. Drug research within the area of infectious diseases even more so, as it involves yet another organism. This might partially explain the small fraction of novel antiparasitic active chemical ingredients approved in the last decades. In 2009, TI Pharma facilitated a multidisciplinary, international consortium aiming at finding a new, safer treatment for human African trypanosomiasis (HAT), commonly known as African sleeping sickness. HAT is caused by the protozoa Trypanosoma brucei (Tbr). Without treatment, all patients entering second stage HAT, spread to the CNS, will die. The available therapies are administered via intravenous or intramuscular injection, placing a heavy cost burden on production, delivery and the point of care. In addition, some are associated with life-threatening toxicity.1 The importance of phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) in the life cycle of Tbr has been validated both genetically and chemically.2 As an example, by modifying rolipram, a fragment-sized hPDE4 inhibitor, a low-affinity inhibitor was identified that led to the generation of a potent TbrPDE inhibitor (VUF13525) with trypanocidal activity.3
1. World Health Organisation, Global Burden of Disease: 2004 Update.
2. Oberholzer et al. FASEB J, 2007, 720-731.
3. Orrling et al Submitted, 2012