Abstract
Ribavirin is a nucleoside analogue with broad antiviral activity. Here we report the synthesis and biological evaluation of novel ribavirin ProTides designed to deliver the bioactive ribavirin monophosphate into cells. Some of the compounds display activity similar to the parent nucleoside against a range of viruses. Enzymatic, cell lysate and preliminary modeling studies have been performed to investigate the lack of enhancement of potency by the ProTides, and these indicate a failure at the final, amino acid cleavage step in the ProTide activation process, leading to inefficient release of the nucleoside monophosphate.
Copyright 2010 Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amides / chemical synthesis
-
Amides / pharmacology
-
Antiviral Agents / chemical synthesis*
-
Antiviral Agents / pharmacology
-
Cell Line
-
Cytopathogenic Effect, Viral
-
Drug Delivery Systems*
-
Drug Design*
-
Humans
-
Indicators and Reagents
-
Magnetic Resonance Spectroscopy
-
Models, Molecular
-
Nerve Tissue Proteins / metabolism
-
Peptides / chemical synthesis
-
Peptides / pharmacology
-
Phosphoric Acids / chemical synthesis
-
Phosphoric Acids / pharmacology
-
Prodrugs / chemical synthesis*
-
Prodrugs / pharmacology
-
Ribavirin / analogs & derivatives*
-
Ribavirin / chemical synthesis*
-
Ribavirin / pharmacology
-
Viruses / drug effects
Substances
-
Amides
-
Antiviral Agents
-
HINT1 protein, human
-
Indicators and Reagents
-
Nerve Tissue Proteins
-
Peptides
-
Phosphoric Acids
-
Prodrugs
-
Ribavirin
-
phosphoramidic acid