Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase ( Tb GAPDH) and Trypanosoma cruzi trypanothione reductase ( Tc TR) and display trypanocidal activity

Uliassi, Elisa; Fiorani, Giulia; Krauth‐Siegel, R. Luise; Bergamini, Christian; Fato, Romana; Bianchini, Giulia; Menéndez, J. Carlos; Molina, Marı́a Teresa; Lopéz-Montero, Eulogio; Falchi, Federico; Cavalli, Andrea; Gul, Sheraz; Kuzikov, Maria; Ellinger, Bernhard; Witt, Gesa; Moraes, Carolina Borsoi; Freitas‐Junior, Lúcio H.; Borsari, Chiara; Costi, Maria Paola; Bolognesi, María Laura

doi:10.1016/j.ejmech.2017.10.005

Cited by 25 publications

(10 citation statements)

References 55 publications

(98 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of Trypanosoma brucei GAPDH ( Tb GAPDH) by GAPDH‐001, as defined by the IC 50 (the concentration at which enzymatic activity is reduced by 50%), was previously reported as 7.2 μM. GAPDH‐001 was reported as non‐competitive (mixed) with NAD + in Tb GAPDH . We therefore determined the IC 50 values of GAPDH‐001 against Ng GAPDH and Ct GAPDH at four concentrations of NAD + .…”

Section: Resultsmentioning

confidence: 99%

“…GAPDH-001 was reported as non-competitive (mixed) with NAD + in TbGAPDH. 26,27 We therefore determined the IC 50 values of GAPDH-001 against NgGAPDH and CtGAPDH at four concentrations of NAD + . The IC 50 values against NgGAPDH measured as 12.4 μM, 7.4 μM, 5.8 μM, and 3.9 μM in the presence of 100 μM, 10 μM, 5 μM, and 1 μM NAD + (Figure 4a, Table 1).…”

Section: Crystal Structures Of Nggapdh and Ctgapdhmentioning

confidence: 99%

See 1 more Smart Citation

Structures of glyceraldehyde 3‐phosphate dehydrogenase in Neisseria gonorrhoeae and Chlamydia trachomatis

et al. 2020

View full text Add to dashboard Cite

Neisseria gonorrhoeae (Ng) and Chlamydia trachomatis (Ct) are the most commonly reported sexually transmitted bacteria worldwide and usually present as co‐infections. Increasing resistance of Ng to currently recommended dual therapy of azithromycin and ceftriaxone presents therapeutic challenges for syndromic management of Ng‐Ct co‐infections. Development of a safe, effective, and inexpensive dual therapy for Ng‐Ct co‐infections is an effective strategy for the global control and prevention of these two most prevalent bacterial sexually transmitted infections. Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is a validated drug target with two approved drugs for indications other than antibacterials. Nonetheless, any new drugs targeting GAPDH in Ng and Ct must be specific inhibitors of bacterial GAPDH that do not inhibit human GAPDH, and structural information of Ng and Ct GAPDH will aid in finding such selective inhibitors. Here, we report the X‐ray crystal structures of Ng and Ct GAPDH. Analysis of the structures demonstrates significant differences in amino acid residues in the active sites of human GAPDH from those of the two bacterial enzymes suggesting design of compounds to selectively inhibit Ng and Ct is possible. We also describe an efficient in vitro assay of recombinant GAPDH enzyme activity amenable to high‐throughput drug screening to aid in identifying inhibitory compounds and begin to address selectivity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Crystal Structures Of Nggapdh and Ctgapdhmentioning

confidence: 99%

Structures of glyceraldehyde 3‐phosphate dehydrogenase in Neisseria gonorrhoeae and Chlamydia trachomatis

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Altogether, the findings reported in this manuscript add EGCG to a growing list of natural products with TR inhibitory activity (Uliassi et al, 2017;Ortalli et al, 2018). We reckon that, by interfering with this enzyme, central to the redox homeostasis of Leishmania spp.…”

Section: A B Cmentioning

confidence: 78%

Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania infantum, Causing Alterations in Redox Balance and Leading to Parasite Death

Inacio

Fonseca

Limaverde-Sousa

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Leishmania infantum is a protozoan parasite that causes a vector borne infectious disease in humans known as visceral leishmaniasis (VL). This pathology, also caused by L. donovani, presently impacts the health of 500,000 people worldwide, and is treated with outdated anti-parasitic drugs that suffer from poor treatment regimens, severe side effects, high cost and/or emergence of resistant parasites. In previous works we have disclosed the anti-Leishmania activity of (-)-Epigallocatechin 3-O-gallate (EGCG), a flavonoid compound present in green tea leaves. To date, the mechanism of action of EGCG against Leishmania remains unknown. This work aims to shed new light into the leishmanicidal mode of action of EGCG. Towards this goal, we first confirmed that EGCG inhibits L. infantum promastigote proliferation in a concentration-dependent manner. Second, we established that the leishmanicidal effect of EGCG was associated with i) mitochondria depolarization and ii) decreased concentration of intracellular ATP, and iii) increased concentration of intracellular H2O2. Third, we found that the leishmanicidal effect and the elevated H2O2 levels induced by of EGCG can be abolished by PEG-catalase, strongly suggesting that this flavonoid kills L. infantum promastigotes by disturbing their intracellular redox balance. Finally, we gathered in silico and in vitro evidence that EGCG binds to trypanothione reductase (TR), a central enzyme of the redox homeostasis of Leishmania, acting as a competitive inhibitor of its trypanothione substrate.

show abstract

“…Most of members of the in-house library were not resynthesized, and their synthetic and characterization data are reported in their respective publications (quinones: memo-quin [45], SVT118 [46], IA5 [48], EU11 [66]; quinazolines and quinolines (CDM38, BAT33, UPR1268) [49][50][51]; stilbenes (ST11 cis/trans) [52]; thiazolidindione (ACG35) [53]; diketopiperazine (JCM24) [54]; tetrahydroacridine (RS34) [55]; dibenzodiazepinone (ADC3); carbazole (ULA26) [56]; steroids (pristimerin, PCM129, UPR1355, digoxin, deslanoside) [57,[60][61][62]; carbamates (URB694, URB913) [58,59]; anilino-alkyl-amides (UCM765, UCM871) [63,64] (Figure 2). One of the selected compounds (DA15) is unpublished, and we report the synthetic procedure below.…”

Section: Chemistrymentioning

confidence: 99%

Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library

et al. 2022

Self Cite

View full text Add to dashboard Cite

The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.

show abstract

Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase ( Tb GAPDH) and Trypanosoma cruzi trypanothione reductase ( Tc TR) and display trypanocidal activity

Cited by 25 publications

References 55 publications

Structures of glyceraldehyde 3‐phosphate dehydrogenase in Neisseria gonorrhoeae and Chlamydia trachomatis

Structures of glyceraldehyde 3‐phosphate dehydrogenase in Neisseria gonorrhoeae and Chlamydia trachomatis

Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania infantum, Causing Alterations in Redox Balance and Leading to Parasite Death

Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library

Contact Info

Product

Resources

About