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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

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Los inhibidores nucleósidos de la transcriptasa inversa poseen una actividad antiinflamatoria intrínseca

Benjamin J Fowler¹, Bradley D Gelfand², Younghee Kim³

¹Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.

Science (New York, N.Y.)

|November 22, 2014

Resumen

Inhibidores nucleosídicos de la transcriptasa inversa (INRTIs) reutilizados para enfermedades impulsadas por P2X7. Estos medicamentos para el VIH inhiben la activación del inflamatorio, mostrando eficacia en modelos de atrofia geográfica e inflamación.

Área de la Ciencia:

Inmunología Inmunología.
Virología Virología.
Oftalmología Oftalmología.

Sus antecedentes:

Los inhibidores nucleosídicos de la transcriptasa inversa (INTR) son tratamientos críticos para el VIH que inhiben la replicación viral.
El ARN Alu activa los inflamatorios P2X7 y NLRP3, lo que lleva a la muerte celular de la retina en la atrofia geográfica, una forma de degeneración macular relacionada con la edad.

Objetivo del estudio:

Investigar el potencial de los NRTIs en el tratamiento de las enfermedades inflamatorias impulsadas por P2X7.
Determinar si los NRTIs pueden inhibir la activación del inflamatorio NLRP3 independiente de su actividad antiviral.

Principales métodos:

Se evaluó la inhibición por NRTI de la activación del inflamatorio NLRP3 mediada por P2X7 inducida por ARN Alu.
Evaluación de la activación de la caspasa-1 como lectura de la actividad inflamatoria.
Eficacia NRTI probada en modelos de ratón de atrofia geográfica, neovascularización coroidal, enfermedad de injerto contra huésped e inflamación estéril del hígado.

Principales resultados:

Los NRTIs inhibieron efectivamente la activación del inflamatorio NLRP3 mediado por P2X7 y la escisión de la caspasa-1 inducida por el ARN Alu.
Esta inhibición se produjo independientemente de la inhibición de la transcriptasa inversa.
NRTIs demostraron efectos terapéuticos en múltiples modelos preclínicos de enfermedades inflamatorias.

Conclusiones:

Los NRTIs poseen potentes propiedades antiinflamatorias al inhibir la vía inflamatoria del P2X7-NLRP3.
La reutilización de fármacos de los NRTIs es una estrategia prometedora para el tratamiento de afecciones inflamatorias impulsadas por P2X7, incluida la atrofia geográfica.

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