Presentazione di PowerPoint

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Uno studio interdisciplinare volto alla scoperta
di nuovi farmaci per le malattie neglette
progettazione e sviluppo di nuovi composti contro
le tripanosomiasi e leishmaniosi Andrea Cavalli,
Maria Laura Bolognesi, Manuela Bartolini,
Federica Belluti, Lorna Piazzi, Michela Rosini,
Francesco Colizzi, Francesca Mancini, Paola Dal
Monte, Elisa Storni, Francesca Cavrini Dipartimen
to di Scienze Farmaceutiche e Dipartimento di
Medicina Clinica Specialistica e Sperimentale
GIORNATE DI FACOLTÀ
29 Ottobre 2007
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The international network
Edinburgh
Rotterdam
Liverpool
Brussels
Montreal
Bordeaux
Zurich
Bologna
Toulouse
Bethesda
Mérida
Yaoundé
Kinshasa
Sao Paulo
Lima
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• Neglected diseases
• Group of tropical infectious diseases, including
  protozoan infections, helminths, and other
  diseases such as leprosy and trachoma
• They include diseases that are prevalent in the
  worlds least developed nations
• Clearly, pharmaceutical industry is unwilling to
  develop medicinal products for these diseases
• The same argument that deters the pharmaceutical
  industry from investing in neglected diseases
  also discourages public research

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• The medicinal chemical approaches
• Structure-based approach based on molecular
  targets that fulfill the following requirements
• the target protein should be essential for the
  survival and/or replication of the parasite
• the selected protein target should differ enough
  from the corresponding human enzyme to ensure
  selectivity
• the 3D structure and mechanistic properties of
  the target should be available in database and in
  literature
• Generation of compounds libraries for
  high-throughput testing by means of whole
  parasitic-cell assays

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The selected molecular targets
Trypanothione reductase (TR)
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
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Structural basis of the TR vs. GR selectivity
TR
GR
Arg347
Ala343
Ala34
Glu19
Arg37
Trp22
Cys63
Met114
Cys58
Asn117
Cys58
Cys53
Tyr114
Tyr111
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The drug discovery process in parasitic disease
Pink R (2005).
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Hit identification
Natural product structural space
Plumbagin antileishmanial and antitrypanosomal
activity
High frequency structural motif
Diospyrin antileishmanial and antitrypanosomal
activity
Library design and synthesis
Lapacol antifungal and antitrypanosomal activity
Phenotipic screening
Inhibitors of parasitic replication
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Analytical tools for drug discovery
Development/selection of new drug candidates
Search for analytical methods and tools rapid and
easy to use
Affinity chromatography using bioreactors based
on immobilized biological targets
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Why IMERs in drug discovery

• IMERs Immobilized Enzyme Reactors
• Low quantity of enzyme required
• Multiple or repetitive use of a single batch of
  enzyme
• Enzymes are usually stabilized by binding
• Potential for fast and automated screening
• Higher accuracy