A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

Cannalire, Rolando; Barreca, Maria Letizia; Manfroni, Giuseppe; Cecchetti, Violetta

doi:10.1021/acs.jmedchem.5b00825

Cited by 50 publications

(22 citation statements)

References 103 publications

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“…Interestingly, several structurally distinct compounds have been identified that inhibit DENV or YFV replication through targeting NS4B (40,(63)(64)(65)(66)(67). In addition, multiple inhibitors of the NS4B protein of hepatitis C virus, a distantly related member of the Flaviviridae family, are currently under preclinical and clinical development for treatment of hepatitis C infection (68). Intriguingly, as summarized in Fig.…”

Section: Discussionmentioning

confidence: 99%

A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

Guo

Julander

et al. 2016

J Virol

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Although a highly effective vaccine is available, the number of yellow fever cases has increased over the past 2 decades, which highlights the pressing need for antiviral therapeutics. In a high-throughput screening campaign, we identified an acetic acid benzodiazepine (BDAA) compound which potently inhibits yellow fever virus (YFV). Interestingly, while treatment of YFV-infected cultures with 2 M BDAA reduced the virion production by greater than 2 logs, the compound was not active against 21 other viruses from 14 different viral families. Selection and genetic analysis of drug-resistant viruses revealed that replacement of the proline at amino acid 219 (P219) of the nonstructural protein 4B (NS4B) with serine, threonine, or alanine conferred YFV with resistance to BDAA without apparent loss of replication fitness in cultured mammalian cells. However, replacement of P219 with glycine conferred BDAA resistance with significant loss of replication ability. Bioinformatics analysis predicts that the P219 amino acid is localized at the endoplasmic reticulum lumen side of the fifth putative transmembrane domain of NS4B, and the mutation may render the viral protein incapable of interacting with BDAA. Our studies thus revealed an important role and the structural basis for the NS4B protein in supporting YFV replication. Moreover, in YFV-infected hamsters, oral administration of BDAA protected 90% of the animals from death, significantly reduced viral load by greater than 2 logs, and attenuated virus infection-induced liver injury and body weight loss. The encouraging preclinical results thus warrant further development of BDAA or its derivatives as antiviral agents to treat yellow fever. IMPORTANCEYellow fever is an acute viral hemorrhagic disease which threatens approximately 1 billion people living in tropical areas of Africa and Latin America. Although a highly effective yellow fever vaccine has been available for more than 7 decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It has been estimated that up to 1.7 million YFV infections occur in Africa each year, resulting in 29,000 to 60,000 deaths. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we identified a benzodiazepine compound that selectively inhibits YFV by targeting the viral NS4B protein. To our knowledge, this is the first report demonstrating in vivo safety and antiviral efficacy of a YFV NS4B inhibitor in an animal model. We have thus reached a critical milestone toward the development of specific antiviral therapeutics for clinical management of yellow fever. Y ellow fever is a mosquito-borne hemorrhagic disease that is frequently associated with jaundice and is caused by yellow fever virus (YFV) infection (1). Vaccination with attenuated YFV-17D vaccine is the most important measurement to prevent yellow fever. The vaccine is safe, affordable, and highly effective, and a single dose of the vaccine is sufficient to confer sustained immunity and lifelong p...

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Section: Discussionmentioning

confidence: 99%

A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

Guo

Julander

et al. 2016

J Virol

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“…A total of 127 RAVs in NS3, NS4B, NS5A, and NS5B were included in the study (Supplementary Table S4 ). RAVs were obtained by merging six recently compiled lists of naturally occurring variants associated with DAA resistance ( Rai and Deval, 2011 ; Bartenschlager et al, 2013 ; Lontok et al, 2015 ; Cannalire et al, 2016 ; Chen et al, 2016 ; Patino-Galindo et al, 2016 ). Specifically, a list of positions where RAVs have been reported was compiled, irrespective of the viral genotype carrying the RAV.…”

Section: Methodsmentioning

confidence: 99%

“…However, DAAs have limited pan-genotypic activity and tend to select for resistance-associated amino acid variants (RAVs) ( Lontok et al, 2015 ). Most RAVs naturally occur in treatment-naive patients and in some instances RAV prevalence differs among genotypes or subtypes ( Rai and Deval, 2011 ; Bartenschlager et al, 2013 ; Lontok et al, 2015 ; Cannalire et al, 2016 ; Chen et al, 2016 ; Patino-Galindo et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Analysis Provides Insight Into the Origin and Adaptation of HCV

et al. 2018

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Hepatitis C virus (HCV) belongs to the Hepacivirus genus and is genetically heterogeneous, with seven major genotypes further divided into several recognized subtypes. HCV origin was previously dated in a range between ∼200 and 1000 years ago. Hepaciviruses have been identified in several domestic and wild mammals, the largest viral diversity being observed in bats and rodents. The closest relatives of HCV were found in horses/donkeys (equine hepaciviruses, EHV). However, the origin of HCV as a human pathogen is still an unsolved puzzle. Using a selection-informed evolutionary model, we show that the common ancestor of extant HCV genotypes existed at least 3000 years ago (CI: 3192–5221 years ago), with the oldest genotypes being endemic to Asia. EHV originated around 1100 CE (CI: 291–1640 CE). These time estimates exclude that EHV transmission was mainly sustained by widespread veterinary practices and suggest that HCV originated from a single zoonotic event with subsequent diversification in human populations. We also describe a number of biologically important sites in the major HCV genotypes that have been positively selected and indicate that drug resistance-associated variants are significantly enriched at positively selected sites. HCV exploits several cell-surface molecules for cell entry, but only two of these (CD81 and OCLN) determine the species-specificity of infection. Herein evolutionary analyses do not support a long-standing association between primates and hepaciviruses, and signals of positive selection at CD81 were only observed in Chiroptera. No evidence of selection was detected for OCLN in any mammalian order. These results shed light on the origin of HCV and provide a catalog of candidate genetic modulators of HCV phenotypic diversity.

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“…Quinoline derivatives represent an important class of heterocyclic compounds utilized as pharmaceuticals (Chu et al, 2019). They possess various biological properties such as antibacterial (Panda et al, 2015), anticancer (Tang et al, 2018), antitubercular (Xu et al, 2017), antiviral (Sekgota et al, 2017), anti-HCV (Cannalire et al, 2016), antimalarial (Hu et al, 2017), anti-Alzheimer's (Bolognesi et al, 2007), antileishmanial (Palit et al, 2009) and anti-inflammatory (Pinz et al, 2016) activities.…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure and Hirshfeld surface analysis of hexyl 1-hexyl-2-oxo-1,2-dihydroquinoline-4-carboxylate

Bouzian¹,

Kansız²,

Mahi³

et al. 2020

Acta Cryst E

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The asymmetric unit of the title compound, C22H31NO3, comprises of one molecule. The molecule is not planar, with the carboxylate ester group inclined by 33.47 (4)° to the heterocyclic ring. Individual molecules are linked by aromaticC—H...Ocarbonyl hydrogen bonds into chains running parallel to [001]. Slipped π–π stacking interactions between quinoline moieties link these chains into layers extending parallel to (100). Hirshfeld surface analysis, two-dimensional fingerprint plots and molecular electrostatic potential surfaces were used to quantify the intermolecular interactions present in the crystal, indicating that the most important contributions for the crystal packing are from H...H (72%), O...H/H...O (14.5%) and C...H/H...C (5.6%) interactions.

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A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

Cited by 50 publications

References 103 publications

A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

Evolutionary Analysis Provides Insight Into the Origin and Adaptation of HCV

Crystal structure and Hirshfeld surface analysis of hexyl 1-hexyl-2-oxo-1,2-dihydroquinoline-4-carboxylate

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