Publication: De péptidos a peptidomiméticos en la búsqueda de inhibidores novedosos de la tripanotión reductasa de Leishmania infantum (Li-TryR)
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2017-03-24
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Universidad Complutense de Madrid
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Abstract
La leishmaniasis es una enfermedad parasitaria causada por un protozoo del género Leishmania y transmitida por la picadura de dípteros de los géneros Lutzomyia y Phlebotomus. A pesar de haber sido descrita por primera vez en 1903 por Leishman y Donovan1, hoy en día sigue siendo un problema de salud pública en más de 88 países, donde hasta 350 millones de personas están en riesgo de contraer la enfermedad. Según la Organización Mundial de la Salud (OMS), se estima que hay 12 millones de infectados, y unos 2 millones de nuevos casos de infección al año entre niños y adultos.2 La leishmaniasis estuvo limitada históricamente a los países cercanos al trópico, pero en los últimos años esta enfermedad se considera una zoonosis emergente en el mundo desarrollado, como es el caso de los EE UU3,4, y ha surgido como infección oportunista ligada a enfermedades crónicas de tipo viral como el síndrome de inmunodeficiencia adquirida (SIDA). Según datos de la OMS, la co-infección con el virus de inmunodeficiencia humana (VIH, agente etiológico del SIDA) se está convirtiendo en una siniestra tendencia global2 (Figura I.1). En personas infectadas por VIH, la leishmaniasis acelera la aparición del SIDA por una inmunosupresión acumulativa, estimulando la replicación del virus...
Leishmaniasis is a neglected tropical disease caused by Leishmania parasite. Although leishmaniasis is emerging nowadays as a worldwide disease, only a limited and outdated drug arsenal for the treatment of leishmaniasis is available. Therefore, there is an urgent need to find new targets and/or inhibition mechanisms for the discovery of inhibitors against these parasite infections. Trypanothione Reductase (TryR) is a validated and an attractive target in the search for new drugs for the treatment of leishmaniasis. This enzyme is exclusive (it does not exist in mammals) and is essential for parasites survival. Since, the biologically functional form of TryR is a homodimer, we have recently reported an alternative inhibition strategy that attempts to disrupt the dimer interface of the homodimer by designing protein-protein interaction inhibitors. By using the recently reported X-ray crystal structure of Leishmania infantum TryR (Li-TryR) and sitedirected mutagenesis we have identified and validated residues E436 and Q439 as "hot spots" for dimer stabilization. These residues are located in an α-helix spanning from P435 to M447...
Leishmaniasis is a neglected tropical disease caused by Leishmania parasite. Although leishmaniasis is emerging nowadays as a worldwide disease, only a limited and outdated drug arsenal for the treatment of leishmaniasis is available. Therefore, there is an urgent need to find new targets and/or inhibition mechanisms for the discovery of inhibitors against these parasite infections. Trypanothione Reductase (TryR) is a validated and an attractive target in the search for new drugs for the treatment of leishmaniasis. This enzyme is exclusive (it does not exist in mammals) and is essential for parasites survival. Since, the biologically functional form of TryR is a homodimer, we have recently reported an alternative inhibition strategy that attempts to disrupt the dimer interface of the homodimer by designing protein-protein interaction inhibitors. By using the recently reported X-ray crystal structure of Leishmania infantum TryR (Li-TryR) and sitedirected mutagenesis we have identified and validated residues E436 and Q439 as "hot spots" for dimer stabilization. These residues are located in an α-helix spanning from P435 to M447...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica I, leída el 01/03/2016