RESUMEN
The design, synthesis, and evaluation of a series of dipeptidyl α-hydroxyphosphonates is reported. The synthesized compounds displayed high anti-norovirus activity in a cell-based replicon system, as well as high enzyme selectivity.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Diseño de Fármacos , Norovirus/efectos de los fármacos , Organofosfonatos/química , Organofosfonatos/farmacología , Infecciones por Caliciviridae/tratamiento farmacológico , Humanos , Simulación del Acoplamiento Molecular , Norovirus/enzimología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED(50) of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.
Asunto(s)
Antivirales/química , Norovirus/enzimología , Péptido Hidrolasas/química , Inhibidores de Proteasas/química , Sulfitos/química , Proteínas Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Células CHO , Cricetinae , Cricetulus , Péptido Hidrolasas/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Sulfitos/síntesis química , Sulfitos/metabolismo , Proteínas Virales/metabolismoRESUMEN
A series of structurally-diverse α-ketoamides and α-ketoheterocycles was synthesized and subsequently investigated for inhibitory activity against norovirus 3CL protease in vitro, as well as anti-norovirus activity in a cell-based replicon system. The synthesized compounds were found to inhibit norovirus 3CL protease in vitro and to also exhibit potent anti-norovirus activity in a cell-based replicon system.
Asunto(s)
Amidas/química , Cisteína Endopeptidasas/química , Compuestos Heterocíclicos/química , Norovirus/enzimología , Péptidos/química , Inhibidores de Proteasas/química , Amidas/farmacología , Cisteína Endopeptidasas/farmacología , Compuestos Heterocíclicos/farmacología , Modelos Moleculares , Estructura Molecular , Norovirus/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
The development of small molecule therapeutics to combat norovirus infection is of considerable interest from a public health perspective because of the highly contagious nature of noroviruses. A series of amino acid-derived acyclic sulfamide-based norovirus inhibitors has been synthesized and evaluated using a cell-based replicon system. Several compounds were found to display potent anti-norovirus activity, low toxicity, and good aqueous solubility. These compounds are suitable for further optimization of pharmacological and ADMET properties.
Asunto(s)
Aminoácidos/química , Aminoácidos/farmacología , Antivirales/química , Antivirales/farmacología , Norovirus/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Aminoácidos/síntesis química , Animales , Antivirales/síntesis química , Infecciones por Caliciviridae/tratamiento farmacológico , Línea Celular , Diseño de Fármacos , Humanos , Sulfonamidas/síntesis químicaRESUMEN
The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine surrogate has been designed and synthesized based on the known substrate specificity of Norwalk virus 3C protease. The inhibitory activity of the compounds with the protease and with a norovirus cell-based replicon system was investigated. Members of this class of compounds exhibited noteworthy activity both in vitro and in a cell-based replicon system.