Trypanosomatid Diseases Molecular Routes to Drug Discovery

This is the first resource to provide researchers in academia and industry with an urgently needed update on drug intervention against trypanosomatides. As such, it
covers every aspect of the topic from basic research findings, via current treatments to translational approaches in drug development and includes both human and livestock diseases. The outstanding editor and contributor team reads like a Who?s Who of the field, thus guaranteeing the outstanding quality of this ready reference.

Series Editor:

Paul M. Selzer studied Biology, Parasitology, and Biochemistry at the University of T?bingen, Germany, where he also received his PhD in Biochemistry on subjects related to the protozoan parasite Trypanosoma brucei. As a post-doctoral fellow he spent three years in the parasitology and tropical disease laboratory of Prof. James H. McKerrow at the University of California, San Francisco (UCSF). Within the Molecular Design Institute at UCSF Dr. Selzer was introduced to modern drug discovery approaches and technologies. He broadened his scientific and business knowledge as a researcher within diverse pharmaceutical companies including Boehringer Mannheim GmbH, Germany, SmithKline Beecham p.l.c., UK, Hoechst Roussel Vet GmbH, Germany, and finally Intervet Innovation GmbH, Germany, a part of Intervet/Schering-Plough Animal Health. Dr. Selzer is also a teacher in Biochemistry, Bioinformatics, and Chemoinformatics at the University of T?bingen in the Department of Biochemistry, which awarded him the title of Professor for his achievements in teaching and research. In 2008, he was also awarded an Honorary Professorship in the Department of Infection and Immunity at the University of Glasgow.



Volume Editors:

Leopold Floh? studied philosophy, medicine and biochemistry and obtained his MD and the venia legendi for Biochemistry from the University of T?bingen, Germany. He served as Scientific Director for Gr?nenthal GmbH in Aachen, the German Biotechnology Centre (GBF, now HZI) in Braunschweig and Molisa GmbH in Magdeburg, Germany, while simultaneously teaching at the local universities. At present, he is chairing the COST Action CM0801 focusing on new drugs for neglected diseases. Leopold Floh? published about 300 scientific papers and was honored with prestigious awards such as a Honorary Degree from the University of Buenos Aires, the Claudius-Galenus-Preis, the Klaus Schwarz Commemorative Medal, the Science and Humanity Price (Oxygen Club of California) and the Trevor Frank Slater Award and Gold Medal (SFRRI).

Timo Jaeger is a graduate of the Technical University of Braunschweig, Germany and completed his PhD in the group of Leopold Floh? with summa cum laude. He worked as a Postdoc at the German Research Centre for Biotechnology, Braunschweig, Germany in the Department for Genome Analysis. In 2004 he joined MOLISA GmbH in Magdeburg, Germany where he served as Head of Biological Research and Development. His research centered on the redox metabolism of pathogens, function and catalytic mechanism of peroxiredoxins, target evaluation, characterization, and drug development against infectious diseases, especially tuberculosis and trypanosomiasis. In 2011 he moved to the Helmholtz Centre for Infection Research in Braunschweig, Germany and is working on the implementation of the German Centre for Infection Research, one of the newly established German Centres for Health Research.

Oliver Koch studied pharmacy at the Philipps-University of Marburg, Germany, where he also received is PhD. He prepared his doctoral thesis in the working group of Prof. Gerhard Klebe at the institute of pharmaceutical chemistry in the field of computer-aided drug design. During this time he also did post-graduate studies in computer science. He worked at the Cambridge Crystallographic Data Centre (CCDC) in Cambridge, UK, as a scientific software engineer before joining the BioChemInformatics/Drug Discovery group at Intervet Innovation GmbH, Germany, in 2008. He is currently working in a cooperation project with Molisa GmbH in Magdeburg, Germany, on the development of new drugs for Tuberculosis and diseases caused by Trypanosomatids.

Part One: Disease Burden, Current Treatments and Medical Needs (including disease models) and strategic approaches:

- History and critical assessment of Drug Discovery towards Kinetoplastida (Duszenko)
-
African Sleeping sickness (Croft)
-
Chagas? Disease (McKerrow)
-
Visceral, mucocutaneous and cutaneous Leishmaniasis (Ilg)
-
Veterinarian diseases (Alunda)
(Each disease to be covered according to the above key words)
-
CDD database (Sean Ekins)
- PPP and Drug Development (DNDi, Rob Don)
- Academic Drug Discovery efforts towards Kinetoplastida (Paul Wyatt, Dundee)


Part Two: Metabolic Peculiarities in the Trypanosomatid Family Guiding Drug
discovery:

- Proteolytic systems (Mottram)
- Gycosomal enzymes (Opperdoes;
- The trypanothione system (Fairlamb)
- Other unusual redox events (Krauth-Siegel)
- The selenoproteom (Gladyshev)
- The kinetoplast kinom (Zilberstein)
- The replicative machinery (Shlomai)
- Isoprenoid Biosynthesis (Urbina)
- RNA metabolism (Clayton)
- Apoptosis- and autophagy-related events (Duszenko)
- Leishmania-host interaction (Moll)
- Kinetoplastida metabolomics (Mike Barrett, Glasgow)
- Kinetoplastida novel transporters and resistance (Harry de Koning, Glasgow)


Part Three: Validation and Prioritization of Drug Targets in Kinetoplasts

- Cruzipain and related proteases (Mottram;
Coombs)
- Peroxiredoxins and related peroxidases (Castro, Tomas;
Wilkinson)
- Protein Kinases (Boshardt)
- Disulfide Reductases (trypanothione reductase, tryparedoxins) (Krauth-Siegel;
Comini)
- Trypanothione synthetase (Comini;
Fyfe;
Fairlamb)
- The glyoxalase system (Cordeiro)
- Enzymes of steroid synthesis (Urbina)
- Myristoyl transferase (Brenk)
- Enzymes of folate metabolism (Fairlamb)
- Glycosomal enzymes (Opperdoes;
- Glucos-6-phosphate dehydrogenase (Comini;
Ortiz)
- Tryp Transporters (Francisco Gamarro, Granada)


Part Four: Examples of structure-based rational design
- Trypanothione reductase inhibitor design (Beig, Selzer, Krauth-Siegel;
Botta)
- Trypanothione synthetase inhibitor design (Koch;
J?ger;
Fairlamb; others)
- Myristoyl transferase inhibitor design (Brenk;
Fairlamb)
- Protease inhibitor design (UCSF, McKerrow, Steverding or Augustyns;
Maes)

Part Five: Compounds under consideration or development


- 1,4-Naphthoquinones (Davioud Charvet)
- 4-Aminoquinolines (Loiseau)
- Antifolates (Costi;
Fairlamb)
- Phosphinic dipeptide inhibitors
- Paullones (Kunick)
- Others (Gamarro;
Robert Jacobs, Scynexis Inc. and Nigel Yarlett, Pace Univ.)
- In vitro and in vivo testing (Reto Brun Basel)