Product inhibition of the hepatitis C virus NS3 protease

Biochemistry
C SteinkühlerR De Francesco

Abstract

The nonstructural protein NS3 of the hepatitis C virus (HCV) harbors a serine protease domain that is responsible for most of the processing events of the nonstructural region of the polyprotein. Its inhibition is presently regarded as a promising strategy for coping with the disease caused by HCV. In this work, we show that the NS3 protease undergoes inhibition by the N-terminal cleavage products of substrate peptides corresponding to the NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B cleavage sites, whereas no inhibition is observed with a cleavage product of the intramolecular NS3-NS4A junction. The Ki values of the hexamer inhibitory products [Ki(NS4A) = 0.6 microM, Ki(NS5A) = 1.4 microM, and Ki(NS4B) = 180 microM] are lower than the Km values of the respective substrate peptides [Km(NS4A-NS4B) = 10 microM, Km(NS5A-NS5B) = 3.8 microM, and Km(NS4B-NS5A) > 1000 microM]. Mutagenesis experiments have identified Lys136 as an important determinant for product binding. The phenomenon of product inhibition can be exploited to optimize peptide inhibitors of NS3 protease activity that may be useful in drug development.

References

Dec 1, 1995·Journal of Virology·E SantoliniN Monica
Aug 1, 1994·Journal of Virology·R BartenschlagerH Jacobsen
Jun 1, 1994·Journal of Virology·E SantoliniN La Monica
Mar 15, 1996·The Journal of Biological Chemistry·C SteinkühlerR De Francesco
Oct 1, 1996·Journal of Virology·C SteinkühlerR De Francesco
Apr 4, 1997·The Journal of Biological Chemistry·A UrbaniA Pessi
Sep 1, 1997·Journal of Virology·L PieroniN La Monica

❮ Previous
Next ❯

Citations

Sep 27, 2002·Biopolymers·Elisabetta Bianchi, Antonello Pessi
Mar 14, 2001·Journal of Peptide Science : an Official Publication of the European Peptide Society·A Pessi
Nov 1, 2003·Bioorganic & Medicinal Chemistry Letters·Robert B PerniYunyi Wei
Jul 26, 2002·Analytical Biochemistry·Christian SteinkühlerSergio Altamura
Oct 31, 2000·Bioorganic & Medicinal Chemistry Letters·M Llinàs-BrunetD Lamarre
Feb 24, 2001·Bioorganic & Medicinal Chemistry Letters·A JohanssonA Hallberg
Mar 20, 2003·Bioorganic & Medicinal Chemistry Letters·Xiaojun ZhangCarl P Decicco
Jan 5, 1999·Bioorganic & Medicinal Chemistry Letters·M Llinàs-BrunetD Lamarre
Nov 5, 2002·Bioorganic & Medicinal Chemistry·Anja JohanssonAnders Hallberg
Nov 25, 2003·Journal of Molecular Graphics & Modelling·Vladimír FrecerStanislav Miertus
Oct 26, 1999·Drug Discovery Today·M A Walker
Oct 16, 2008·Biochemistry·Suzanne M Tomlinson, Stanley J Watowich
Aug 19, 2005·Nature·Raffaele De Francesco, Giovanni Migliaccio
Apr 12, 2000·Journal of Viral Hepatitis·R De FrancescoC Steinkühler
May 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Michael Z LinRoger Y Tsien
Nov 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Keith P RomanoCelia A Schiffer
Sep 12, 2012·The Journal of Biological Chemistry·Jonas KüglerJohn Collins
May 12, 2010·The Journal of Biological Chemistry·Kevin D RaneyCraig E Cameron
Aug 23, 2002·Protein Science : a Publication of the Protein Society·Annarita CasbarraElisabetta Bianchi
Jan 11, 2000·Clinical Microbiology Reviews·P LeyssenJ Neyts
Feb 14, 2004·Journal of Virology·Eugene V AgapovCharles M Rice
Mar 25, 2014·World Journal of Gastroenterology : WJG·Cristiane Valle TovoPaulo Roberto Lerias de Almeida
Jan 23, 2014·Journal of Medicinal Chemistry·Åsa RosenquistMaria Beumont-Mauviel
Jan 31, 2003·Expert Opinion on Investigational Drugs·Frank NarjesChristian Steinkühler
Jul 29, 2003·Expert Opinion on Investigational Drugs·Michelle P WalkerZhi Hong

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.