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Los inhibidores de pirimidina actúan en sinergia con los análogos nucleósidos para bloquear el SARS-CoV-2
David C Schultz1, Robert M Johnson2, Kasirajan Ayyanathan3
1Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. dschultz@pennmedicine.upenn.edu.
Nature
|February 7, 2022
Resumen
Los investigadores examinaron 18,000 medicamentos contra el SARS-CoV-2, y identificaron 122 con actividad antiviral. La combinación de análogos de nucleósidos con inhibidores de pirimidina muestra efectos sinérgicos contra el COVID-19, ofreciendo una estrategia terapéutica prometedora.
Área de la Ciencia:
- Virología
- Descubrimiento de drogas
- Biología molecular
Sus antecedentes:
- El SARS-CoV-2 ha causado millones de muertes en todo el mundo, con una necesidad significativa de tratamientos antivirales efectivos más allá de las vacunas.
- Las variantes emergentes representan una amenaza, lo que requiere el desarrollo de nuevas terapias que puedan superar la evasión de las vacunas.
- Las opciones terapéuticas actuales para el COVID-19 son limitadas, lo que pone de relieve la urgencia del descubrimiento de medicamentos antivirales de amplio espectro.
Objetivo del estudio:
- Para examinar una gran biblioteca de medicamentos para la actividad antiviral contra el SARS-CoV-2.
- Identificar nuevos compuestos antivirales, en particular los análogos de nucleósidos y los agentes dirigidos al huésped.
- Evaluar los efectos sinérgicos de las terapias combinadas contra la infección por SARS-CoV-2.
Principales métodos:
- Cribado de aproximadamente 18,000 medicamentos que usan SARS-CoV-2 vivo en las células respiratorias humanas.
- Validación de la actividad antiviral y la selectividad de los fármacos candidatos identificados.
- Pruebas in vitro e in vivo de combinaciones sinérgicas de inhibidores de la biosíntesis de la pirimidina y análogos de nucleósidos.
Principales resultados:
- 122 medicamentos demostraron actividad antiviral y selectividad contra el SARS-CoV-2.
- Se identificaron 16 análogos de nucleósidos entre los compuestos activos, incluidos los antivirales aprobados como remdesivir y molnupiravir.
- La terapia combinada de inhibidores de la biosíntesis de pirimidina y análogos de nucleósidos mostró una inhibición sinérgica del SARS-CoV-2, incluso contra cepas emergentes.
Conclusiones:
- Se ha identificado un número significativo de medicamentos antivirales potenciales contra el SARS-CoV-2 a través de pruebas de detección a gran escala.
- Dirigirse a las vías de biosíntesis de nucleósidos del huésped presenta una estrategia viable para desarrollar antivirales de amplio espectro.
- Las combinaciones sinérgicas de agentes antivirales existentes y nuevos ofrecen una estrategia clínica prometedora para controlar el COVID-19 y las posibles amenazas virales futuras.
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