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El ajuste de la cinética de extracción de esteroles produce un antifúngico de polieno que preserva los riñones
Arun Maji1,2,3,4, Corinne P Soutar2,3,5, Jiabao Zhang2,3
1Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nature
|November 8, 2023
Resumen
Desarrollando nuevos fármacos antifúngicos, los investigadores descubrieron que dirigirse a la extracción de ergosterol fúngico, no a las membranas celulares, conduce a antifúngicos de polieno potentes y ahorradores de riñones como AM-2-19.
Área de la Ciencia:
- Química medicinal
- Micología
- Farmacología
Sus antecedentes:
- El desarrollo antifúngico tradicional de polieno se basó en un modelo de permeabilización de membrana defectuoso.
- La anfotericina B, un antifúngico vital, causa toxicidad renal al extraer esteroles de las membranas celulares.
- La extracción de ergosterol por hongos, no la ruptura de la membrana, es el mecanismo principal de la acción antifúngica de la anfotericina B.
Objetivo del estudio:
- Desarrollar agentes antifúngicos de polieno potentes y que ahorren los riñones.
- Comprender y mitigar la toxicidad renal asociada con la anfotericina B.
- Para diseñar racionalmente nuevos antifúngicos ajustando la dinámica de la interacción molecular.
Principales métodos:
- Investigó el mecanismo de los efectos antifúngicos y tóxicos de la anfotericina B.
- Se utilizó un análisis estructural de alta resolución de los complejos de anfotericina B-sterol.
- Diseñó y sintetizó derivados estructurales de la anfotericina B, incluida la AM-2-19, y evaluó su eficacia y toxicidad.
Principales resultados:
- Se identificó la extracción de colesterol como el factor de la toxicidad renal de la anfotericina B.
- Desarrolló un derivado de ahorro renal (AM-2-19) que extrae selectivamente y rápidamente el ergosterol fúngico sin unirse al colesterol.
- AM- 2-19 demostró una potente actividad antifúngica, evasión de la resistencia y eficacia en modelos preclínicos de infecciones fúngicas invasivas.
Conclusiones:
- El diseño racional basado en la dinámica de interacción molecular puede producir terapias antifúngicas mejoradas.
- Dirigirse a la extracción de ergosterol ofrece una estrategia prometedora para desarrollar antifúngicos potentes, seguros y evasivos de la resistencia.
- El nuevo polieno AM-2-19 representa un avance significativo en el tratamiento de infecciones fúngicas potencialmente mortales.
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