X-ray Crystallography Contributions to Drug Discovery Against Parasite

Pozzi, Cecilia; Tassone, Giusy; Mangani, Stefano

doi:10.1016/bs.armc.2018.08.005

Cited by 8 publications

(14 citation statements)

References 60 publications

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“…TbPTR1 in complex with pyrrolopyrimidine-based compounds (Tulloch et al, 2010;Khalaf et al, 2014;Pozzi et al, 2018). Although this scaffold is only a poor inhibitor of TbPTR1 (K i > 35 mM; Tulloch et al, 2010), some of its derivatives were effective in blocking the enzyme activity, with more than 20 compounds showing K i app values of <0.5 mM (Khalaf et al, 2014).…”

Section: Figurementioning

confidence: 99%

“…3). Furthermore, the extended tricyclic aromatic system of 1 is -sandwiched between the cofactor nicotinamide and Phe97, mimicking an interaction that is crucial for substrate recognition and catalysis by PTR enzymes (Gourley et al, 2001;Schü ttelkopf et al, 2005;Pozzi et al, 2018).…”

Section: Figurementioning

confidence: 99%

“…The TbPTR1 inhibitors developed to date were conceived as substrate-competitive inhibitors and are based on a wide variety of scaffolds, including 2,4-diaminopteridine (Dawson et al, 2006;Tulloch et al, 2010), quinazoline (Dawson et al, 2010), 2,4-diaminopyrrolopyrimidine (Tulloch et al, 2010), chromone (Borsari et al, 2016;Di Pisa et al, 2017), 2-aminothiadiazole (Linciano et al, 2017), 2-aminobenzimidazole (Mpamhanga et al, 2009), triazine (Tulloch et al, 2010), 1,6-dihydrotriazine (Landi et al, 2019) and 2-aminobenzothiazole (Linciano et al, 2019). More than 60 crystal structures of TbPTR1-inhibitor complexes have now been deposited in the Protein Data Bank (PDB), clarifying the key binding interactions that occur inside the catalytic cavity (Pozzi et al, 2018). Bicyclic aromatic systems (such as pteridines, quinolines, pyrrolopyrimidines, benzimidazoles and benzothiazoles), which are able to mimic the substrate pterin moiety, have been extensively exploited as molecular scaffolds for the development of TbPTR1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor

Landi

Linciano

Tassone

et al. 2020

Acta Cryst Sect D Struct Biol

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The protozoan parasite Trypanosoma brucei is the etiological agent of human African trypanosomiasis (HAT). HAT, together with other neglected tropical diseases, causes serious health and economic issues, especially in tropical and subtropical areas. The classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by the expression of pteridine reductase 1 (PTR1). The combined inhibition of PTR1 and DHFR activities in Trypanosoma parasites represents a promising strategy for the development of new effective treatments for HAT. To date, only monocyclic and bicyclic aromatic systems have been proposed as inhibitors of T. brucei PTR1 (TbPTR1); nevertheless, the size of the catalytic cavity allows the accommodation of expanded molecular cores. Here, an innovative tricyclic-based compound has been explored as a TbPTR1-targeting molecule and its potential application for the development of a new class of PTR1 inhibitors has been evaluated. 2,4-Diaminopyrimido[4,5-b]indol-6-ol (1) was designed and synthesized, and was found to be effective in blocking TbPTR1 activity, with a K i in the low-micromolar range. The binding mode of 1 was clarified through the structural characterization of its ternary complex with TbPTR1 and the cofactor NADP(H), which was determined to 1.30 Å resolution. The compound adopts a substrate-like orientation inside the cavity that maximizes the binding contributions of hydrophobic and hydrogen-bond interactions. The binding mode of 1 was compared with those of previously reported bicyclic inhibitors, providing new insights for the design of innovative tricyclic-based molecules targeting TbPTR1.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor

Landi

Linciano

Tassone

et al. 2020

Acta Cryst Sect D Struct Biol

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“…Targeting the enzymes of the folate metabolism was proven as a successful strategy against bacterial infections [ 13 ] and malaria [ 14 ], and, more recently, it has been exploited also for the development of novel antiparasitic treatments [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Trypanosomes are unable to synthesize folates and pterins required for critical cellular metabolic pathways, such as the biosynthesis of nucleic acids and proteins [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…The pteridine and pyrimidine core structures have largely been explored with the intent to discover new anti-trypanosomatidic drugs, also taking advantage of the information derived from the available crystal structures, which allowed the further decoration of their scaffolds [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Pursuing our interest in the search of more effective agents against the T. brucei parasite, we deemed worthwhile the study of the anti-trypanosomatidic activity of two known drugs, pyrimethamine (PYR) and MTX ( Figure S1 , Supplementary Materials ).…”

Section: Introductionmentioning

confidence: 99%

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

et al. 2021

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Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.

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Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors

et al. 2019

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Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was developed, resulting in 1 and 2a having IC50 values of 692 and 186 nM, respectively, toward TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, in vitro cell-growth-inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.

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X-ray Crystallography Contributions to Drug Discovery Against Parasite

Cited by 8 publications

References 60 publications

High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor

High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors

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