Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure-Activity Relationships. Drug Des Devel Ther 2020;14:757-771
Date
03/12/2020Pubmed ID
32158194Pubmed Central ID
PMC7048954DOI
10.2147/DDDT.S201089Scopus ID
2-s2.0-85079831753 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
BACKGROUND: 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.
METHODS: 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].
RESULTS: 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 active site binding. MPPs were also active against three common protease mutants (T54A, A156T, and V36M) with equivalent or better IC50 values as compared to wild type enzyme.
CONCLUSION: These findings document the versatility of MPPs as antiviral agents with an expanded sensitivity for HCV genotypes and resistance to some common viral mutations. The results also suggest that further study of MPP structure and function will be useful for the development of new antiviral agents.
Author List
Hu K, Zhu Z, Mathahs MM, Tran H, Bommer J, Testa CA, Schmidt WNAuthor
Katherine Hu MD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antiviral AgentsCells, Cultured
Dose-Response Relationship, Drug
Hepacivirus
Humans
Microbial Sensitivity Tests
Molecular Structure
Protease Inhibitors
Serine Proteases
Structure-Activity Relationship
Viral Nonstructural Proteins
Virus Replication
