Discovery and Development of Simeprevir (TMC435), a HCV NS3/4A Protease Inhibitor

Rosenquist, Åsa; Samuelsson, Bertil; Johansson, Per-Ola; Cummings, Maxwell D.; Lenz, Oliver; Raboisson, Pierre; Simmen, Kenny; Vendeville, Sandrine; Kock, Herman de; Nilsson, Magnus; Horváth, András; Kalmeijer, Ronald; Rosa, Guy De La; Beumont–Mauviel, Maria

doi:10.1021/jm401507s

Cited by 182 publications

(150 citation statements)

References 74 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…Despite its considerable effect on HCV 164 genotype 2, inhibition was not observed on HCV genotype 3 replication. So far, all NS3 protease 165 inhibitors available have also no effect on HCV genotype 3 (Gentile et al, 2014;Hayashi et al, 166 2014;Rosenquist et al, 2014;Summa et al, 2012). Altogether, the hypothesis that Fac4 is 167 interfering with NS3 protease is strengthened.…”

Section: Discussion 150mentioning

confidence: 99%

Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4

Campos

Bittar

Jardim

et al. 2017

Journal of General Virology

View full text Add to dashboard Cite

18Hepatitis C Virus (HCV) affects about 170 million people worldwide. The current treatment has 19 a high cost and variable response rates according to the virus genotype. Acridones, a group of 20 compounds extracted from natural sources, showed potential antiviral actions against HCV. 21Thus, this study aimed to evaluate the effect of a panel of 14 synthetic acridones on the HCV life 22 cycle. The compounds were screened using an Huh7.

show abstract

Section: Discussion 150mentioning

confidence: 99%

Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4

Campos

Bittar

Jardim

et al. 2017

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…Nowadays the NSOC therapy for genotype 1, chronic HCV infection is the use of BOC or TVR in combination with INF-α-peg and RBV [37][38][39][40] . Additionally, two other direct antiviral drugs (DAAs), simeprevir (protease-inhibitor) [41] and sofosbuvir (nucleotide analogue of the NS5B RNApolymerase) [42] [43][44][45][46][47] .…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus genetic variability and evolution

Echeverría

Moratorio

Cristina

et al. 2015

WJH

View full text Add to dashboard Cite

Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a singlestranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection. Hepatitis C virus genetic variability and evolution no preventive vaccine, and though antiviral therapy has been improved in the past few years, not all patients eradicate the virus as a result of it. The main reason lies in the intrinsic genetic variability that characterises RNA viruses, such as HCV, whose RNA polymerase lacks proof-reading activity, leading to a high mutation rate and the generation of a wide range of genome variants better known as a quasispecies. Therefore this review summarises current data on HCV quasispecies dynamics, antiviral therapy and recombination events.Echeverría N, Moratorio G, Cristina J, Moreno P. Hepatitis C virus genetic variability and evolution. World J Hepatol 2015; 7(6): 831845 Available from:

show abstract

“…To the best of our knowledge, this type of sulfonimidation has not been reported previously. Considering the importance of sulfonimides as important bioisosteres of carboxylic aicds in medicinal chemistry, [17][18][19][20] we decided to explore the scope and limitation of such a ring-opening reactions. Scheme 2.…”

Section: Resultsmentioning

confidence: 99%

Sulfonimidation via ring-opening of 2-oxazolines with acidic sulfonimide nucleophiles

Gutiérrez¹,

Dean²,

Laxamana³

et al. 2016

Arkivoc

View full text Add to dashboard Cite

Acidic sulfonimide nucleophiles including dibenzenesulfonimide, o-benzenesulfonimide, dimethanesulfonimide, and N-(methylsulfonyl)-benzenesulfonamide are discovered to open a variety of alkyl-, aryl-and heteroaryl-2-oxazoline rings to provide the sulfonimidation products in refluxing 1,4-dioxane. The electron-rich 2-oxazoline substrates worked well for the nucleophilic ring-opening reactions while no reaction took place for the electron-poor 2-oxazoline substrates.

show abstract

Discovery and Development of Simeprevir (TMC435), a HCV NS3/4A Protease Inhibitor

Cited by 182 publications

References 74 publications

Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4

Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4

Hepatitis C virus genetic variability and evolution

Sulfonimidation via ring-opening of 2-oxazolines with acidic sulfonimide nucleophiles

Contact Info

Product

Resources

About