Folates in Trypanosoma brucei: Achievements and Opportunities

Cullia, Gregorio; Tamborini, Lucia; Conti, Paola; Micheli, Carlo De; Pinto, Andrea

doi:10.1002/cmdc.201800500

Cited by 13 publications

(16 citation statements)

References 57 publications

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“…Furthermore, structural variation in the core ring structures of antifolates is common, where pteridine, pyrimidine, pyridopyramidines, quinazoline and pyridopyrimidine rings have all featured on active compounds . T. brucei express a fused DHFR‐thymidylate synthase (DHFR‐TS) in addition to pteridine reductase 1 (PTR1) …”

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…Despite the extensive design and development efforts to obtain potent and selective inhibitors of PTR1 and DHFR, there is often limited transferability of on-target-based activity to an in vitro or even in vivo activity against T. brucei or T. cruzi. For a more detailed overview on the efforts made, possible reasons for this limitation and other potential targets to be considered in the future, the reader is referred to the recent review by Cullia et al (2018).…”

Section: Folate Metabolismmentioning

confidence: 99%

Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

Calogeropoulou¹,

Magoulas²,

Pöhner³

et al. 2019

Medicinal Chemistry of Neglected and Tropical Diseases

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The Neglected Tropical Diseases (NTDs) are a group of 17 pathologies, recognized by the World Health Organization (WHO), which are endemic in 149 countries of tropical and subtropical areas of the globe, and affect more than one billion people overall (Feasey et al. 2010). The pathologies are all caused by microparasites or macroparasites. Among the diseases provoked by microparasites, three are caused by kinetoplastidae, a group of flagellated protozoa transmitted by insect vectors: Chagas disease, Human African Trypanosomiasis and leishmaniasis. The focus of the present chapter is on the identification of new drugs for the treatment of trypanosomatidic infections such as Chagas disease, caused by Trypanosoma cruzi, and Human African Trypanosomiasis, caused by Trypanosoma brucei (Filardy et al. 2018).

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“…[13][14][15][16] It provides reduced folates, which are crucial to biological processes like DNA, protein and amino acid synthesis or one-carbon transfer. 14,17,18 . In Trypanosomatids, DHFR inhibition was found to be ineffective due to a metabolic bypass via the biopterin-reducing pteridine reductase 1 (PTR1, Figure 1): When DHFR is inhibited, PTR1, which can also reduce folates, is overexpressed and sustains sufficient metabolite levels to ensure parasite survival.…”

Section: Introductionmentioning

confidence: 99%

Multitarget, Selective Compound Design Yields Picomolar Inhibitors of a Kinetoplastid Pteridine Reductase 1

Pöhner¹,

Quotadamo²,

Panecka-Hofman³

et al. 2020

Preprint

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The optimization of compounds with multiple targets in the drug discovery cycle is a difficult multidimensional problem. Here, we present a systematic, multidisciplinary approach to the development of selective anti-parasitic compounds. Efficient microwave-assisted synthesis of pteridines along with iterations of crystallographic structure determination were used to validate computational docking predictions and support derivation of a structure-activity relationship for multitarget inhibition. This approach yielded compounds showing picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, along with selective submicromolar inhibition of parasitic dihydrofolate reductase (DHFR). Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei, whilst retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.

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Folates in Trypanosoma brucei: Achievements and Opportunities

Cited by 13 publications

References 57 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

Multitarget, Selective Compound Design Yields Picomolar Inhibitors of a Kinetoplastid Pteridine Reductase 1

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