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Novel lead compounds in pre-clinical development against African sleeping sickness



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Med. Chem. Commun., 2017, 8,1872-1890
DOI: 10.1039/C7MD00280G, Review Article
Michael Berninger, Ines Schmidt, Alicia Ponte-Sucre, Ulrike Holzgrabe
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

 Author affiliations


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.

Image result for University of Würzburg Ulrike Holzgrabe

  • 1974 – 1981
    Studied chemistry and pharmacy at Marburg University and Kiel University
  • 1990 – 1999
    C3 professor at the University of Bonn, Germany
  • 1994 – 1995
    Visiting professor at the University of Erlangen-Nuremberg, Germany, and the University of Illinois at Chicago, USA
  • 1997 – 1999
    Vice-rector for teaching, studies and study reform at the University of Bonn
  • Since 1999
    C4/W3 professor of pharmaceutical chemistry at the University of Würzburg, Germany
  • Since 2009
    Dean 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
 Image result for University of Würzburg Michael Berninger
Image result for University of Würzburg Michael Berninger
Image result for University of Würzburg Michael Berninger
Image result for University of Würzburg Institute of Pharmacy and Food Chemistry
Image result for University of Würzburg Institute of Pharmacy and Food Chemistry
Image result for University of Würzburg Institute of Pharmacy and Food Chemistry
Image result for University of Würzburg Institute of Pharmacy and Food Chemistry
///////////University of Würzburg,  Ulrike Holzgrabe

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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