DOI: 10.1039/C7MD00280G, Review Article
This article reviews the recent progress in drug development against the African sleeping sickness.
Novel lead compounds in pre-clinical development against African sleeping sickness
Abstract
Human African trypanosomiasis (HAT), also known as African sleeping sickness, is caused by parasitic protozoa of the genus Trypanosoma. As the disease progresses, the parasites cross the blood brain barrier and are lethal for the patients if the disease is left untreated. Current therapies suffer from several drawbacks due to e.g. toxicity of the respective compounds or resistance to approved antitrypanosomal drugs. In this review, the different strategies of drug development against HAT are considered, namely the target-based approach, the phenotypic high throughput screening and the drug repurposing strategy. The most promising compounds emerging from these approaches entering an in vivo evaluation are mentioned herein. Of note, it may turn out to be difficult to confirm in vitro activity in an animal model of infection; however, possible reasons for the missing efficacy in unsuccessful in vivo studies are discussed.
Conclusion There are various starting points to generate hit compounds for the treatment of African sleeping sickness. Especially stage II of HAT which is very hard to treat poses a tough challenge for drug discovery programs as molecules inevitably need to cross the BBB. However, promising compounds (2, 15, and 17) are in the pipeline accomplishing these criteria for CNS mouse models, and in some cases even are orally bioavailable (15 and 17). Especially the large phenotypic screening campaigns performed by the GNF, GlaxoSmithKline, DDU, and Sykes et al. resulted in promising hits discussed herein. Nevertheless, it is not always easy to translate results from in vitro studies into in vivo efficacy like shown in several of the mentioned studies. The reasons for in vivo failures are multilayered and might originate from (I) extensive metabolism, (II) high plasma protein binding, (III) poor water solubility, (IV) efflux transporters, (V) different sensitivity for particular strains, (VI) reduced permeability, and (VII) growth inhibition rather than trypanocidal effects.
Nominated by
- German Research Foundation (DFG)
- AcademiaNet member since 17.05.2010
- AcademiaNet- Selection Criteria
Employed by
- Julius-Maximilians-Universität Würzburg
Academic Discipline/Fields
- Natural sciences/ Engineering/ Agricultural sciences
Field
Chemistry
Area of specialisation
Medical chemistry and pharmaceutical analysis
Research interests
- Development of new anti-infective substances
- Development of subtype-selective ligands of muscarinic receptors (for treating Alzheimer’s and pain)
- Quality analysis of medicinal drugs and excipients (exposing sham medications)
Distinctions and Awards
- Offered the presidency of the German Federal Institute for Drugs and Medical Devices (BfArM), 2009 (declined)
- Offer of a C4 professorship at Freie Universität (FU) Berlin, Germany, 2004 (declined)
- Lesmüller travel grant, 2001
- 3rd Lesmüller Lecture, 2000
- Wolfgang Pauli Prize, 1999
- Phoenix Science Prize, 1999
- Offers of C4 professorships at the Universities of Tübingen and Münster, Germany, 1998 (declined)
- Offer of a C3 professorship at Freie Universität (FU) Berlin, Germany, 1990 (declined)
- Faculty award from Kiel University, 1984
Interested in
- Management position, Membership in scientific bodies
Languages
English, German
Doctorate
- 1983: Untersuchungen zur Konformation und Konfiguration heterocyclischer Bicyclo[3.3.1]nonanone und ihrer Reduktionsprodukte (summa cum laude) (“Investigations of the conformation and configuration of heterocyclic bicyclo[3.3.1]nonanones and their reduction products (summa cum laude)”)
PostDoc qualification, e.g. Habilitation
- 1989: Oxidative Cyclisierung von ß-Aminoketonen mit Cer(IV)sulfat zu 1,2,3,4-Tetrahydroisochinolinen in Pharmazeutischer Chemie (“Oxidative cyclisation of ß-aminoketones with cerium(IV) sulphate to 1,2,3,4-tetrahydroisoquinolines in pharmaceutical chemistry”)
Short CV/Education and training
-
1974 – 1981Studied chemistry and pharmacy at Marburg University and Kiel University
-
1990 – 1999C3 professor at the University of Bonn, Germany
-
1994 – 1995Visiting professor at the University of Erlangen-Nuremberg, Germany, and the University of Illinois at Chicago, USA
-
1997 – 1999Vice-rector for teaching, studies and study reform at the University of Bonn
-
Since 1999C4/W3 professor of pharmaceutical chemistry at the University of Würzburg, Germany
-
Since 2009Dean of the Faculty of Chemistry and Pharmacy at the University of Würzburg
![]()
Selected publications
- Mohr, K. et al.: Rational design of dualsteric GPCR ligands: quests and promise. In: Br. J. Pharmacol. 159, 2010. pp. 997-1008.
- Antony, J. et al.: Dualsteric GPCR targeting: a novel route to binding and signalling pathway selectivity. In: FASEB J. 23, 2009. pp. 442-450 (Listed as a “Must Read” by the “Faculty of 1000 Biology – the expert guide to the most important advances in biology”).
- Niedermeier, S. et al.: A small-molecule inhibitor of Nipah virus envelope protein-mediated membrane fusion. In: J. Med. Chem. 52, 2009. pp. 4257-4265.
- Göbel, T. et al.: In search of novel agents for therapy of tropical diseases and human immunodeficiency virus. In: J. Med. Chem. 51, 2008. pp. 238-250.
- Hörr, V. et al.: Laser-induced fluorescence-capillary electrophoresis and fluorescence microplate reader measurement: two methods to quantify the effect of antibiotics. In: Anal. Chem. 79, 2007. pp. 7510-7518 (reviewed by D.L. Shenkenberg in Biophotonics International, Dec. 2007, pp. 57-58).
- Disingrini, T. et al.: Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors. In: J. Med. Chem. 49, 2006. pp. 366-372.
![]()
Selected projects
- Characterisation of the oncogenic signalling network in multiple myeloma: development of targeted therapies, clinical research group KFO 216, inhibitors of the HSF/HSP system for treating multiple myeloma, since 2009
- Identification, preparation and functional analysis of active ingredients for combating infectious diseases, SFB 630, small molecules for treating tropical infectious diseases, since 2003
- Allosteric modulators and subtype-selective ligands of the muscarinic receptors, since 1991
![]()
Membership in scientific bodies/juries
- German Research Foundation (DFG) review-board member at the University of Würzburg, Germany, since 2009
- Member of the Board of Pharmaceutical Science, International Federation of Pharmacy (FIP), since 2008
- Member of the executive committee, European Federation for Pharmaceutical Sciences (Eufeps), since 2007
- President of the German Pharmaceutical Society, 2004 – 2007
- Member of the board of trustees of the University of Bonn, Germany, 2003 – 2007
- Member of the scientific advisory board, German Federal Institute for Drugs and Medical Devices (BfArM), since 2002
- Member of the German and European pharmacopoeia commissions, as well as president of several German and European pharmacopoeia boards, since 2001
Filed under: Uncategorized Tagged: African Sleeping Sickness, Ulrike Holzgrabe, University of Würzburg
