Boceprevir: A Protease Inhibitor for the Treatment of Hepatitis C

Chang, Mei Chi; Gordon, Lori A.; Fung, Horatio B.

doi:10.1016/j.clinthera.2012.08.009

Cited by 28 publications

(15 citation statements)

References 69 publications

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“…In the particular case of HIV-infected patients, this aspect is important because the interactions with antiretroviral treatment will have to be added to the drawbacks of the new protease inhibitors, along with a higher rate of adverse events and the cost of treating HIV/HCV coinfected patients, which could render universal therapy unaffordable for public health systems [3], [16], [26], [27]. In our study, 39% of HIV-infected patients coinfected by HCV genotype 1 achieved a SVR, similar to other series [10], [15], [24], [28], [29], [30].…”

Section: Discussionmentioning

confidence: 99%

Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

et al. 2014

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ObjectiveTo establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism).Patients and MethodsA sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, −238 TNF-α and −592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count.ResultsPatients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of −238 TNF-α genotype GG was detected in patients with significant liver fibrosis.ConclusionsIn HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a −238 TNF-α polymorphism in these patients.

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Section: Discussionmentioning

confidence: 99%

Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

et al. 2014

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“…HCV patients can be treated with telaprevir or boceprevir HCV PI for 12 to 44 weeks (27,28). Due to the inhibition of HCV replication, the levels of NS3 · 4A protein will ultimately be insufficient to cleave newly synthesized IPS-1 and TRIF, restoring the IFN signaling pathway.…”

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confidence: 99%

Restoration of the Activated Rig-I Pathway in Hepatitis C Virus (HCV) Replicon Cells by HCV Protease, Polymerase, and NS5A Inhibitors In Vitro at Clinically Relevant Concentrations

Kalkeri

Lin

Gopilan

et al. 2013

Antimicrob Agents Chemother

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Hepatitis C virus (HCV) is a hepatotropic virus that belongs to the family Flaviviridae. Chronic HCV infection can result in fibrosis, cirrhosis, and hepatocellular carcinoma (1). It is estimated that approximately 2% of the world population (ϳ170 million people) is infected with HCV, making it a major world health concern (2-6). The HCV genome consists of a positive-strand RNA molecule of approximately 9,600 nucleotides encoding both structural and nonstructural proteins. Nonstructural proteins 3 (NS3) and 5B (NS5B) have serine protease and RNA-dependent RNA polymerase functions, respectively, which are essential for proteolytic processing of the nonstructural-protein region of the HCV polyprotein and for viral RNA replication.Because the HCV polymerase and protease are necessary for the viral replication cycle, both have been attractive targets for anti-HCV drug development (7). Several inhibitors of the NS3 · 4A protease (e.g., Incivek In addition to being essential for proteolytic cleavage of the viral polyprotein, the HCV NS3 · 4A protease has also been shown to suppress the innate immune response by cleaving beta interferon (IFN-␤) stimulator 1 (IPS-1) (13) and Toll/interleukin 1 (IL-1) receptor domain-containing adapter inducing IFN-␤ (TRIF) (14) in cultured cells. In response to viral replication intermediates, such as viral RNA and proteins, IPS-1 and TRIF adaptor protein act as signaling intermediates in retinoic acidinducible gene (Rig-I) and/or Toll-like receptor 3 (TLR3) pathways (15-17). Activation of these pathways induces IRF3 activation and subsequent transcriptional activation of type I

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“…Experiments were performed three times in triplicate (or sextuplicate in the case of DMSO-treated cells). The HCV protease inhibitor boceprevir served as a positive control (36).…”

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confidence: 99%

Novel Dengue Virus NS2B/NS3 Protease Inhibitors

Wang

Bock

Snitko

et al. 2015

Antimicrob Agents Chemother

128

107

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Dengue fever is a severe, widespread, and neglected disease with more than 2 million diagnosed infections per year. The dengue virus NS2B/NS3 protease (PR) represents a prime target for rational drug design. At the moment, there are no clinical PR inhibitors (PIs) available. We have identified diaryl (thio)ethers as candidates for a novel class of PIs. Here, we report the selective and noncompetitive inhibition of the serotype 2 and 3 dengue virus PR in vitro and in cells by benzothiazole derivatives exhibiting 50% inhibitory concentrations (IC 50 s) in the low-micromolar range. Inhibition of replication of DENV serotypes 1 to 3 was specific, since all substances influenced neither hepatitis C virus (HCV) nor HIV-1 replication. Molecular docking suggests binding at a specific allosteric binding site. In addition to the in vitro assays, a cell-based PR assay was developed to test these substances in a replication-independent way. The new compounds inhibited the DENV PR with IC 50 s in the low-micromolar or submicromolar range in cells. Furthermore, these novel PIs inhibit viral replication at submicromolar concentrations. Dengue viruses (DENVs) are enveloped positive-strand RNA viruses and belong to the family Flaviviridae. DENV is the most important arthropod-borne viral infection. Over one-third of the world population lives in areas of DENV endemicity, and an estimated 390 million infections occur every year. In addition, the number of countries having experienced DENV epidemics has risen from 9 in 1970 to more than 100 today (1, 2). Furthermore, the number of diagnosed infections across America, Southeast Asia, and the Western Pacific nearly doubled from 1.2 million in 2008 to over 2.3 million in 2010 (2). Four different DENV serotypes have been identified so far. Recently, evidence for an additional subtype has been presented (3). Serotypes 1 to 4 are now prevalent in Asia, Africa, and America, and the regions where dengue is endemic are still increasing (4-6), with dengue endangering even Europe and the United States due to vector spread. DENV infections can be associated with dengue fever, but up to 88% of the infections remain inapparent (7). These nonpersistent infected patients serve besides persistently infected mosquitoes as a virus reservoir. Severe DENV infections and especially reinfections may lead to dengue hemorrhagic fever and dengue shock syndrome, with lethality up to 5% (2,8,9). There is neither a vaccination nor a specific treatment for DENV infections.The DENV genome contains a single open reading frame, which encodes the structural proteins capsid, membrane precursor (prM), and envelope and the nonstructural proteins NS1, NS2, NS3, NS4, and NS5 (10). Cellular proteases and the viral serine protease (PR) are responsible for cleaving the viral precursor polyprotein into functional proteins. The DENV PR consists of the amino-terminal domain of the NS3 protein and requires NS2B, a 14-kDa protein, as a cofactor to form a stable complex. This heterodimeric PR cleaves at the capsid-prM, NS2A/NS2...

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Boceprevir: A Protease Inhibitor for the Treatment of Hepatitis C

Cited by 28 publications

References 69 publications

Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

Restoration of the Activated Rig-I Pathway in Hepatitis C Virus (HCV) Replicon Cells by HCV Protease, Polymerase, and NS5A Inhibitors In Vitro at Clinically Relevant Concentrations

Novel Dengue Virus NS2B/NS3 Protease Inhibitors

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