Discovery of new dual targeting chimeric inhibitors of PTR1- DHFR from trypanosomatidic parasites
Projects
Discovery of new dual targeting chimeric inhibitors of PTR1- DHFR from trypanosomatidic parasites
European Lead Factory-Lygature
Period: 2022- 2023 experiments finalized
Status: 2024 follow-up - ongoing
Participants: MPCosti, (Unimore) Sheraz Gul (Fraunofher-Hamburg), Anabela Cordeiro (I3S, Porto), C. Pozzi, University of Siena
Pteridine reductase (PTR1) is a well-known target in antiparasitic drug discovery emerged from drug resistance studies in Leishmania infantum parasite [1]. As one of the important enzyme in the folate metabolic pathway, it is present only in the Trypanosmatidic parasites therefore it is considered a specie-specific drug target. Medicinal chemistry approaches considered the parasitic dihydrofolate reductase (DHFR) enzyme as an optimal partner for PTR1 to achieve an efficient antiparasitic activity. Combination of inhibitors targeting the two enzymes or single inhibitor with dual inhibition activity of the same were considered the best strategy to follow (ref). However, the mechanistic basis of the combined inhibition is still unclear because the interplay PTR1-DHFR using the same substrate, dihydrofolic acid (DHF) is not an obvious event. As a change of paradigm, we proposed to identify PTR1 inhibitors inactive towards the parasitic DHFR to be used as a drug/probe for deeper molecular studies or novel drug discovery program. We started a collaborative project with the European Lead Factory (ELF) supported by Innovative Medicine Initiative (IMI) with the aim to develop on target high throughput screening discovery of low nanomolar, Leishmania infantum PTR1 inhibitors showing 103-104 selectivity index against DHFR. The programme was performed following the ELF development track by including a progressive assays/molecular properties/full profile testing and validation and final re-synthesis of the selected hits. We successfully obtained the compounds with the expected profile.
The best compounds are under evaluation for their antiparasitic activity. X-ray crystal structures have been obtained and new medicinal chemistry programs are under development.
References [1] Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development. A Cavazzuti et al. PNAS 2008, 1448. [2]. Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections. P. Linciano et al. Journal of Medicinal Chemistry 2019 62, 3989. [3]. The European lead factory—an experiment in collaborative drug discovery Hugh Laverty et al. Journal of medicines development sciences 2015, 1, 20.