RESUMEN
Despite the rising threat of fatal coronaviruses, there are no general proven effective antivirals to treat them. 2-Aminoquinazolin-4(3H)-one derivatives were newly designed, synthesized, and investigated to show the inhibitory effects on SARS-CoV-2 and MERS-CoV. Among the synthesized derivatives, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (9g) and 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4 (3H)-one (11e) showed the most potent anti-SARS-CoV-2 activities (IC50 < 0.25 µM) and anti-MERS-CoV activities (IC50 < 1.1 µM) with no cytotoxicity (CC50 > 25 µM). In addition, both compounds showed acceptable results in metabolic stabilities, hERG binding affinities, CYP inhibitions, and preliminary PK studies.
Asunto(s)
Antivirales/síntesis química , Diseño de Fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Quinazolinonas/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/virología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Ratones , Microsomas/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/aislamiento & purificación , Quinazolinonas/química , Quinazolinonas/metabolismo , Quinazolinonas/uso terapéutico , Ratas , SARS-CoV-2/aislamiento & purificación , Relación Estructura-Actividad , Tratamiento Farmacológico de COVID-19RESUMEN
Remdesivir was recently approved to treat COVID-19. While this antiviral agent delivers clinical benefits, several safety concerns in many cases have been raised. This study reports that remdesivir at nanomolar concentrations inhibits carboxylesterase-2 (CES2) through covalent modifications. CES2 is a major drug-metabolizing enzyme. The combination of high potency with irreversible inhibition concludes that cautions must be exercised when remdesivir is used along with drugs hydrolyzed by CES2.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/farmacología , Carboxilesterasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Adenosina Monofosfato/efectos adversos , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/efectos adversos , Alanina/farmacología , Alanina/uso terapéutico , Antivirales/efectos adversos , Antivirales/uso terapéutico , Carboxilesterasa/metabolismo , Interacciones Farmacológicas , Humanos , Microsomas/metabolismo , Preparaciones Farmacéuticas/metabolismo , Tenofovir/metabolismo , Tratamiento Farmacológico de COVID-19RESUMEN
Coronavirus E protein is a small membrane protein found in the virus envelope. Different coronavirus E proteins share striking biochemical and functional similarities, but sequence conservation is limited. In this report, we studied the E protein topology from the new SARS-CoV-2 virus both in microsomal membranes and in mammalian cells. Experimental data reveal that E protein is a single-spanning membrane protein with the N-terminus being translocated across the membrane, while the C-terminus is exposed to the cytoplasmic side (Ntlum/Ctcyt). The defined membrane protein topology of SARS-CoV-2 E protein may provide a useful framework to understand its interaction with other viral and host components and contribute to establish the basis to tackle the pathogenesis of SARS-CoV-2.