Activity of Bisnaphthalimidopropyl Derivatives against Trypanosoma brucei

Graça, Nuno A. G.; Gaspar, Luís; Costa, David; Loureiro, Inês; Lin, Paul Kong Thoo; Ramos, Isbaal; Roura, Meritxell; Pruvost, Alain; Pemberton, Ian K.; Loukil, Hadjer; MacDougall, Jane; Tavares, Joana; Cordeiro-da-Silva, Anabela

doi:10.1128/aac.02490-15

Cited by 7 publications

(4 citation statements)

References 25 publications

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“…Parasites. Throughout the experiments parasites used include Plasmodium berghei ANKA strain clone 676cl1 expressing a GFP-Luciferase fusion gene via the pbef1 α promoter [21], Trypanosoma brucei brucei Lister 427 expressing the redshifted luciferase gene (PpyRE9h) flanked by 5′VSG/3′tubulin [20], [22], a cloned line of Leishmania infantum (MHOM/MA/67/ITMAP-263) expressing luciferase under the control of the intergenic region of α-tubulin [23].…”

Section: Methodsmentioning

confidence: 99%

In vivo imaging of pathogen homing to the host tissues

Tavares

Costa

Teixeira

et al. 2017

Methods

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Hematogenous dissemination followed by tissue tropism is a characteristic of the infectious process of many pathogens including those transmitted by blood-feeding vectors. After entering into the blood circulation, these pathogens must arrest in the target organ before they infect a specific tissue. Here, we describe a non-invasive method to visualize and quantify the homing of pathogens to the host tissues. By using in vivo bioluminescence imaging we quantify the accumulation of luciferase-expressing parasites in the host organs during the first minutes following their intravascular inoculation in mice. Using this technique we show that in the malarial infection, once in the blood circulation, most of bioluminescent Plasmodium berghei sporozoites, the parasite stage transmitted to the host skin by a mosquito bite, rapidly home to the liver where they invade and develop inside hepatocytes. This homing is specific to this developmental stage since blood stage parasites do not accumulate in the liver, as well as extracellular Trypanosoma brucei bloodstream forms and liver-infecting Leishmania infantum amastigotes. Finally, this method can be used to study the dynamics of tissue tropism of parasites, dissect the molecular and cellular basis of their increased arrest in organs and to evaluate immune interventions designed to block this targeted interaction.

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Section: Methodsmentioning

confidence: 99%

In vivo imaging of pathogen homing to the host tissues

Tavares

Costa

Teixeira

et al. 2017

Methods

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“…T . brucei Sir2rp1 (accession number: AAX70528.1) tagged with a C-terminal hexahistidine was expressed and characterized essentiality as described previously [ 50 ] L . infantum Sir2rp1 was expressed and purified as previously described [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease

et al. 2018

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Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region’s leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.

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“…Our groups' previous results demonstrating activity toward L. infantum led to the testing of BNIPs as inhibitors of the related Trypanosomatid T. brucei and its Sir2rp1 orthologue, TbSir2rp1 [202]. BNIPs revealed to be very potent inhibitors of in vitro parasite growth, with one of the compounds, BNIPDabut (Figure 1)withanEC 50 in the range of the reference drug pentamidine.…”

Section: Naphtalimide Derivatives As Potential Drugs For Chagas Diseamentioning

confidence: 99%

“…Although BNIPDabut maintained a strong trypanocidal activity in vivo, as assessed by the decrease in bioluminescent signals to levels similar to those of the reference drug control pentamidine, it was not sufficient for infection clearance, as animals' parasitaemia relapsed shortly after treatment interruption. Nevertheless, BNIPDabut should constitute a scaffold for further consideration in HAT drug discovery [202].…”

Section: Naphtalimide Derivatives As Potential Drugs For Chagas Diseamentioning

confidence: 99%

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

Gaspar¹,

Smith²,

Moretti³

et al. 2018

Chagas Disease - Basic Investigations and Challenges

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Human trypanosomiasis is a neglected tropical disease caused by protozoan parasites of the genus Trypanosoma. Trypanosoma brucei is responsible for sleeping sickness, also called African trypanosomiasis, while Trypanosoma cruzi causes Chagas disease, or American trypanosomiasis. Together, these diseases are responsible for significant mortality, morbidity and lost productivity in the endemic regions. There are no vaccines and treatments rely on drugs with limited efficacy, high cost, serious side effects and long administration periods. Since these diseases affect mostly the poor, there is no economic interest in the development of new drugs by pharmaceutical companies, and hopes for new treatments rely on public initiatives, public-private partnerships or philanthropic programs. The first step in the discovery of new drugs involves the identification of active molecules as starting points for further development, by either employing whole cells or by specific molecular target screenings. Research efforts undertaken by the authors' groups have focused on exploiting both strategies in the search for new molecules for trypanosomiasis drug discovery. In this chapter, we focus on Chagas disease and the recently uncovered potential of using sirtuins as targets for infection control.

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Activity of Bisnaphthalimidopropyl Derivatives against Trypanosoma brucei

Cited by 7 publications

References 25 publications

In vivo imaging of pathogen homing to the host tissues

In vivo imaging of pathogen homing to the host tissues

Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

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