Plasmodium falciparum Apicoplast Drugs: Targets or Off-Targets?

Botté, Cyrille Y.; Dubar, Faustine; McFadden, Geoffrey I.; Maréchal, Éric; Biot, Christophe

doi:10.1021/cr200258w

Cited by 87 publications

(88 citation statements)

References 142 publications

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“…In primary chloroplasts, DHAP is known to be exported to the cytosol by the triose phosphate/ phosphate translocator (TPT) in exchange for inorganic phosphate (Pi) needed to regenerate ATP in the stroma. In the secondary plastid of Apicomplexa (organisms presenting a plastid limited by four membranes, as in Eustigmatophyceae, but lacking photosynthesis), TPT translocators act in the opposite way, importing DHAP to feed the nonmevalonate pathway of isoprenoid synthesis and FA synthesis (Mullin et al, 2006;Brooks et al, 2010;Botté et al, 2012Botté et al, , 2013. We identified four genes coding for TPTs in N. gaditana (Naga_100100g11, Naga_101308g1, Naga_100006g37, and Naga_100007g104), and at least one of these genes has high homology with the Apicomplexa TPT (Naga_100100g11), showing conserved features such as 10 membrane-spanning domains and a chloroplastic transit peptide, suggesting a likely similar role in importing DHAP into the plastid.…”

Section: Metabolic Regulation By Modulation Of Intercellular Transportmentioning

confidence: 99%

Light Remodels Lipid Biosynthesis in Nannochloropsis gaditana by Modulating Carbon Partitioning between Organelles

et al. 2016

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The seawater microalga Nannochloropsis gaditana is capable of accumulating a large fraction of reduced carbon as lipids. To clarify the molecular bases of this metabolic feature, we investigated light-driven lipid biosynthesis in Nannochloropsis gaditana cultures combining the analysis of photosynthetic functionality with transcriptomic, lipidomic and metabolomic approaches. Light-dependent alterations are observed in amino acid, isoprenoid, nucleic acid, and vitamin biosynthesis, suggesting a deep remodeling in the microalgal metabolism triggered by photoadaptation. In particular, high light intensity is shown to affect lipid biosynthesis, inducing the accumulation of diacylglyceryl-N,N,N-trimethylhomo-Ser and triacylglycerols, together with the up-regulation of genes involved in their biosynthesis. Chloroplast polar lipids are instead decreased. This situation correlates with the induction of genes coding for a putative cytosolic fatty acid synthase of type 1 (FAS1) and polyketide synthase (PKS) and the down-regulation of the chloroplast fatty acid synthase of type 2 (FAS2). Lipid accumulation is accompanied by the regulation of triose phosphate/inorganic phosphate transport across the chloroplast membranes, tuning the carbon metabolic allocation between cell compartments, favoring the cytoplasm, mitochondrion, and endoplasmic reticulum at the expense of the chloroplast. These results highlight the high flexibility of lipid biosynthesis in N. gaditana and lay the foundations for a hypothetical mechanism of regulation of primary carbon partitioning by controlling metabolite allocation at the subcellular level.

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Section: Metabolic Regulation By Modulation Of Intercellular Transportmentioning

confidence: 99%

Light Remodels Lipid Biosynthesis in Nannochloropsis gaditana by Modulating Carbon Partitioning between Organelles

et al. 2016

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“…Pycnidione is structurally similar to atovaquone, an ingredient of the antimalarial medication Malarone ® , which is comprised of atovaquone and proguanil hydrochloride (Wright & Lang-Unnasch 2005). Molecules isolated from the marine sponge Plakortis simplex, such as polyketide cycloperoxides, and from the sponge Xestospongia sp., such as xestoquinone, have antiplasmodial activity (Botté et al 2012), as do compounds taken from fertile soils, which exhibit sesquiterpene-related antimalarial activity (Koeni 2003).…”

Section: Strategies Used To Discover New Antimalarial Drugs -A Searchmentioning

confidence: 99%

New approaches in antimalarial drug discovery and development: a review

Aguiar

Rocha

Souza

et al. 2012

Mem. Inst. Oswaldo Cruz

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Malaria remains a major world health problem following the emergence and spread of Plasmodium falciparum that is resistant to the majority of antimalarial drugs. This problem has since been aggravated by a decreased sensitivity of Plasmodium vivax to chloroquine. This review discusses strategies for evaluating the antimalarial activity of new compounds in vitro and in animal models ranging from conventional tests to the latest high-throughput screening technologies. Antimalarial discovery approaches include the following: the discovery of antimalarials from natural sources, chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases and molecular modelling using virtual screening technology and docking. Using these approaches, thousands of new drugs with known molecular specificity and active against P. falciparum have been selected. The inhibition of haemozoin formation in vitro, an indirect test that does not require P. falciparum cultures, has been described and this test is believed to improve antimalarial drug discovery. Clinical trials conducted with new funds from international agencies and the participation of several industries committed to the eradication of malaria should accelerate the discovery of drugs that are as effective as artemisinin derivatives, thus providing new hope for the control of malaria

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“…En cambio valores positivos de indican un carácter hidrofobico y por lo tanto alta capacidad de atravesar la membrana. 49 Como se observa en la ecuación 18 el signo negativo en la variable LogP o/w , sugiere que el aumento en el carácter lipofilico disminuye la actividad biológica de los N-óxidos de quinoxalina, las moléculas con valores muy altos del coeficiente de partición octanol/agua (LogP o/w > 5) tienden a ser poco solubles en la membrana debido a que exceden la regla de lipinsky, 55 lo anterior podría explicar la relación inversa entre el carácter lipofilico y la actividad biológica de los compuestos estudiados.…”

Section: (18)unclassified

2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE

Guerra¹,

López²,

Figueredo³

et al. 2016

Química Nova

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publicado na web em 06/05/2016 2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE. In the present work was performed a quantitative structure-activity relationship (QSAR) for a set of derivatives of 1,4-quinoxaline N-oxides with antichagasic activity based on reactivity descriptors from the frame conceptual DFT. QSAR models showed a good statistical quality and capacity internal prediction with R 2 > 0.6 and Q 2 > 0.5 respectively. QSAR model suggest that antichagasic activity of the studied compounds depends largely from the reactive behavior of N-oxide group (N-O). Also, reactivity descriptors showed that the N-oxide group is a reactive site in theses derivatives with nucleophilic characteristics. The results QSAR shed light on the understanding of the mechanism of action and design of new drugs based on derivatives of 1,4-di-N-oxides quinoxaline.Keywords: QSAR; Antichagasic; N-oxide group; Nucleophilic. INTRODUCCIONLa enfermedad de Chagas fue descubierta en 1909 por el medico brasileño Carlos Chagas mientras diagnosticaba a una joven paciente de dos años que presentaba parásitos en el torrente sanguíneo.1 Esta enfermedad, producida por el parásito protozoario Trypanosoma cruzi (T. cruzi), afecta actualmente entre 6 y 8 millones de personas en el mundo, 2 siendo endémica en América latina. No obstante, su incidencia en el continente europeo y algunos países de Norteamérica ha aumentado en los últimos años debido a los patrones de migración que provocan la diseminación de la enfermedad. 3,4 Aunque el principal modo de transmisión de T. cruzi hacia el ser humano ocurre por contacto con las heces de algunos hematófagos triatominos, 5 existen otros modos de infección asociados a transfusiones sanguíneas, 6 trasplantes de órganos, 7,8 contacto entre madre e hijo durante el parto, 9 y por vía oral. 10Con respecto a las manifestaciones clínicas, existen dos etapas que caracterizan la enfermedad de Chagas. La primera etapa comienza justo después de la infección (fase aguda), y aunque es asintomática, se han reportado casos con síntomas similares a los de una infección febril, dificultando así su correcto diagnóstico. 11La segunda etapa (fase crónica), que puede tardar hasta 15 años en aparecer, se caracteriza por cardiomiopatía dilatada 12,13 y afecciones del tracto digestivo 14 que representan un alto riesgo comprometiendo la vida de los pacientes. Desde el punto de vista farmacológico, el tratamiento actual de la enfermedad de Chagas se basa principalmente en dos fármacos nitro-heterocíclicos llamados Nifurtimox (Nfx) y benznidazol (Bz), descubiertos empíricamente entre 1960 y 1970; mostrando una efectividad en casi el 60% de los casos que son tratados durante la fase aguda. Sin embargo, el uso de Nfx y Bz para el tratamiento de la enfermedad durante la frase crónica es controversial debido a que estos nitro-heterociclos solo son eficaces contra la forma extracelular de T. cruzi que se desarrolla durante la fase aguda. Por lo tanto, la búsqueda de nuevos fármacos más...

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Plasmodium falciparum Apicoplast Drugs: Targets or Off-Targets?

Cited by 87 publications

References 142 publications

Light Remodels Lipid Biosynthesis in Nannochloropsis gaditana by Modulating Carbon Partitioning between Organelles

Light Remodels Lipid Biosynthesis in Nannochloropsis gaditana by Modulating Carbon Partitioning between Organelles

New approaches in antimalarial drug discovery and development: a review

2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE

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