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Inhibidores covalentes reversibles dirigidos a las lisinas con largo tiempo de permanencia
Rahi M Reja1, Wenjian Wang1, Yuhan Lyu1
1Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467, United States.
Journal of the American Chemical Society
|January 18, 2022
Resumen
Los investigadores desarrollaron una nueva conjugación de lisina reversible utilizando una nueva diazaborina, creando inhibidores covalentes reversibles de acción prolongada. Este enfoque ralentiza significativamente la disociación, superando la química de iminoboronato anterior para la inhibición de la sortasa.
Área de la Ciencia:
- Química medicinal
- La bioquímica
- Biología Química
Sus antecedentes:
- Los inhibidores covalentes reversibles ofrecen ventajas sobre los medicamentos tradicionales al proporcionar un compromiso sostenido con el objetivo.
- La química existente del iminoboronato permite una inhibición covalente reversible, pero puede sufrir una cinética de disociación rápida.
- La sortaza estafilocócica es un objetivo validado para el desarrollo antimicrobiano, crucial para la virulencia bacteriana.
Objetivo del estudio:
- Introducir una nueva ojiva formadora de diazaborina (RMR1) para la conjugación reversible de lisina.
- Evaluar la eficacia de RMR1 como componente de los inhibidores covalentes reversibles de acción prolongada contra la estafilococosortasa.
- Comparar la cinética de disociación de la nueva química de la diazaborina con la química existente del iminoboronato.
Principales métodos:
- Síntesis y caracterización de la nueva ojiva formadora de diazaborina, RMR1.
- Conjugación de RMR1 con un ligando peptídico dirigido a la estafilococosortasa.
- Ensayos bioquímicos y basados en células para evaluar la inhibición de la sortasa y la eficacia del compuesto.
- Estudios cinéticos comparativos de inhibidores basados en RMR1 frente a los inhibidores basados en iminoboronato.
Principales resultados:
- El nuevo producto de diazaborina presenta una cinética de disociación significativamente más lenta en comparación con los iminoboronatos.
- Los ligandos peptídicos conjugados con RMR1 muestran una inhibición potente y de acción prolongada de la estafilococosortasa.
- La eficacia se confirmó tanto en ensayos bioquímicos in vitro como en experimentos basados en células.
Conclusiones:
- La ojiva formadora de diazaborina RMR1 representa un avance significativo en el diseño de inhibidores covalentes reversibles.
- La modulación de la cinética de disociación de enlaces es una estrategia clave para desarrollar inhibidores covalentes reversibles de acción prolongada y eficaces.
- Esta nueva química es prometedora para el desarrollo de nuevas terapias dirigidas a la sortasa bacteriana y potencialmente a otras enzimas.
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