Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure-Activity Relationships
Abstract
Antiviral actions of tetrapyrroles have been described in a number of systems. Our goal was to evaluate antagonism of the HCV NS3-4A protease by a variety of common porphyrins and characterize structure-activity relationships that may be useful for future drug design of HCV and related Flaviviruses. Using fluorometric assays, common metalloprotoporphyrins (MPP) all inhibited NS3-4A protease with IC50 values in low micromolar ranges [CoPP (1.4 µM) < ZnPP = MnPP = SnPP < CuPP < FePP (6.5 µM) = protoporphyrin]. Lineweaver-Burk plots confirmed that MPP: NS3 inhibition was basically competitive. All tested MPPs inhibited HCV genotype 1A, 1B, 2A and 3A recombinant proteases with the same fidelity suggesting wide antagonistic capabilities. However, when the MPPs were tested in cellular incubations with HCV replicons only Zn, Fe and free-base protoporphyrin showed comparable EC50 and IC50 values suggesting that there may be critical differences in MPP uptake and intracellular availability. Meso, deutero, and isohematoporphyrin derivatives, with or without metal substitution, all showed less anti-protease and antiviral activities as compared to protoporphyrins, suggesting that the planar, vinyl side chains are important for protease act...Continue Reading
References
Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C Virus.
Citations
Methods Mentioned
Software Mentioned
Related Concepts
Related Feeds
Antivirals
Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.
Antivirals (ASM)
Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.