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Methods to Investigate the Regulatory Role of Small RNAs and Ribosomal Occupancy of Plasmodium falciparum
Published on: December 4, 2015
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Estructura y resistencia a los medicamentos del transportador de Plasmodium falciparum PfCRT
Jonathan Kim1, Yong Zi Tan1,2, Kathryn J Wicht3
1Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
Nature
|November 29, 2019
Resumen
La resistencia a los medicamentos en el paludismo por Plasmodium falciparum es un gran desafío. Este estudio revela la estructura atómica del transportador PfCRT, explicando cómo las mutaciones causan resistencia a la cloroquina y la piperaquina, medicamentos antimalarios clave.
Área de la Ciencia:
- Biología estructural
- Parasitología
- Descubrimiento de drogas
Sus antecedentes:
- El Plasmodium falciparum resistente a los medicamentos obstaculiza los esfuerzos de control y eliminación de la malaria.
- La resistencia a la cloroquina (CQ) y a la piperaquina (PPQ) está relacionada con mutaciones en el transportador PfCRT.
- La comprensión del mecanismo de PfCRT es crucial para el desarrollo de nuevos medicamentos contra la malaria.
Objetivo del estudio:
- Para determinar la estructura atómica del transportador PfCRT de los parásitos resistentes a las drogas.
- Aclarar los mecanismos moleculares subyacentes a la resistencia a la CQ y a la PPQ.
- Proporcionar información sobre la resistencia a los medicamentos contra la malaria para el desarrollo terapéutico futuro.
Principales métodos:
- Microscopía crioelectrónica de una sola partícula (cryo-EM) con una resolución de 3,2 Å.
- Tecnología de fragmento de unión al antígeno (Fab) para la determinación estructural.
- Ensayos de unión y transporte in vitro, estudios funcionales y análisis in silico.
Principales resultados:
- Se determinó la estructura de la isoforma PfCRT de parásitos sensibles al CQ y al PPQ.
- Las mutaciones que confieren resistencia se localizan en una cavidad central, el sitio primario de interacción del fármaco.
- PfCRT transporta CQ pero no PPQ; las mutaciones específicas permiten el transporte y la resistencia de PPQ.
Conclusiones:
- Las características estructurales y las diferencias mecánicas distintas median la resistencia a CQ y PPQ.
- El estudio proporciona información a nivel atómico sobre los mecanismos de resistencia a los medicamentos contra la malaria.
- Los hallazgos son críticos para comprender los fallos del tratamiento y diseñar los medicamentos antimaláricos de próxima generación.
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