We have previously identified low nanomolar PTR1 inhibitors effectively working against Leishmaniaand Trypanosome parasites, in vitro in a synergistic mode with known classical antifolates. We haveobtained at the moment at least two x-ray structure of the protein-inhibitor complexes that indicate that punctual modification of the bound ligand can be performed to improve the affinity.Pteridine reductase 1 is a validated target for combination therapy directed to the folate metabolismpathway in Leishmania major (Lm) and Tripanosoma cruzi (Tc). The inhibition of the enzyme, highlyspecific for parasite with respect to human cell, can help in the complete block of the parasite growth.Based on these results the aim of the present project is directed ì) to develop enzyme inhibitors with improved affinity for the PTR1 enzyme and low affinity/high affinity for the DHFR enzyme, to do this we take advantage of structure-based drug design strategy and chemistry development; ii) to develop the best leads so far obtained in terms of pharmacokinetic propertiesthrough in vitro/in vivo model studies; iii) to evaluate the two inhibitors so far obtained in in vivo animal model, taking advantage of the WHO evaluation service.
|Titolo:||Optimization and development of antifolates as antileishmania and antitrypanosome agents. WHO- A50599|
|Autori:||M.P. COSTI; A.CAVAZZUTI|
|Data di pubblicazione:||2005|
|Appare nelle tipologie:||Partecipazione a progetti di ricerca|
File in questo prodotto:
I documenti presenti in Iris Unimore sono rilasciati con licenza Creative Commons Attribuzione - Non commerciale - Non opere derivate 3.0 Italia, salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris