Novel peptidyl α-aminoalkylphosphonates as inhibitors of hepatitis C virus NS3/4A protease

Marcin Skoreński; Magdalena Pachota; Krzysztof Pyrć; Marcin Sieńczyk; Józef Oleksyszyn

doi:10.1016/j.antiviral.2017.06.020

Novel peptidyl α-aminoalkylphosphonates as inhibitors of hepatitis C virus NS3/4A protease

Antiviral Res. 2017 Aug:144:286-298. doi: 10.1016/j.antiviral.2017.06.020. Epub 2017 Jun 30.

Authors

Marcin Skoreński¹, Magdalena Pachota², Krzysztof Pyrć², Marcin Sieńczyk¹, Józef Oleksyszyn³

Affiliations

¹ Wroclaw University of Technology, Faculty of Chemistry, Division of Medicinal Chemistry and Microbiology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland.
² Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
³ Wroclaw University of Technology, Faculty of Chemistry, Division of Medicinal Chemistry and Microbiology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland. Electronic address: jozef.oleksyszyn@pwr.edu.pl.

PMID: 28673801
DOI: 10.1016/j.antiviral.2017.06.020

Abstract

Herein, we describe the synthesis and application of novel phosphonic inhibitors designed to target the NS3/4A protease, which is crucial for the life cycle of hepatitis C virus. We examined the inhibitory potency of our synthesized compounds against two genotypes (1a and 1b) of NS3/4A protease and four mutant strains of HCV. The most potent inhibitors displayed k₂/K_I values of 79 850 M^-1s^-1 and 60 850 M^-1s^-1 against genotype 1a and 1b protease, respectively. Further in vitro evaluation of the most potent inhibitors revealed that vastly reduced HCV replication. Cellular toxicity, plasma stability, reactivity with selected human proteases as well the stability of inhibitor-protease complex and its intracellular availability are also discussed.

Keywords: Hepatitis C virus; NS3/4A protease; Peptidyl phosphonates; Serine protease inhibitors.

MeSH terms

Antiviral Agents / isolation & purification
Antiviral Agents / pharmacology*
Antiviral Agents / toxicity
Carrier Proteins / antagonists & inhibitors*
Cell Line
Cell Survival / drug effects
Hepacivirus / drug effects*
Hepacivirus / enzymology*
Hepacivirus / physiology
Humans
Intracellular Signaling Peptides and Proteins
Organophosphonates / isolation & purification
Organophosphonates / pharmacology
Organophosphonates / toxicity
Serine Proteinase Inhibitors / isolation & purification
Serine Proteinase Inhibitors / pharmacology*
Serine Proteinase Inhibitors / toxicity
Viral Nonstructural Proteins / antagonists & inhibitors*
Virus Replication / drug effects

Substances

Antiviral Agents
Carrier Proteins
Intracellular Signaling Peptides and Proteins
NS3 protein, hepatitis C virus
NS4A cofactor peptide, Hepatitis C virus
Organophosphonates
Serine Proteinase Inhibitors
Viral Nonstructural Proteins