Small molecule inhibition of hepatitis C virus E2 binding to CD81

VanCompernolle, Scott E.; Wiznycia, Alexander V.; Rush, Jeremy R.; Dhanasekaran, M.; Baures, Paul W.; Todd, Scott C.

doi:10.1016/s0042-6822(03)00406-9

Cited by 66 publications

(64 citation statements)

References 45 publications

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“…CD81 0 s participation in cell invasion and its contribution to liver damage make it an important target for new anti-HCV therapeutics. Some of the first inhibitors designed to block the E2:CD81-LEL interaction were CD81 mimics developed by VanCompernolle et al [20]. Small molecules were designed to mimic the solvent exposed hydrophobic ridge of helix D in the CD81-LEL domain and were found to bind HCV E2 reversibly and to competitively block the binding of E2 to CD81 [20].…”

Section: Introductionmentioning

confidence: 99%

“…Some of the first inhibitors designed to block the E2:CD81-LEL interaction were CD81 mimics developed by VanCompernolle et al [20]. Small molecules were designed to mimic the solvent exposed hydrophobic ridge of helix D in the CD81-LEL domain and were found to bind HCV E2 reversibly and to competitively block the binding of E2 to CD81 [20]. This was the first direct demonstration that CD81 is an important receptor in HCV entry [20].…”

Section: Introductionmentioning

confidence: 99%

“…Small molecules were designed to mimic the solvent exposed hydrophobic ridge of helix D in the CD81-LEL domain and were found to bind HCV E2 reversibly and to competitively block the binding of E2 to CD81 [20]. This was the first direct demonstration that CD81 is an important receptor in HCV entry [20]. In addition, the mutational studies conducted by Higginbottom et al [17] and Drummer et al [19] identified the key amino acid residues that contribute to the E2:CD81-LEL interaction.…”

Section: Introductionmentioning

confidence: 99%

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Identification of ligands that target the HCV-E2 binding site on CD81

Olaby

Azzazy

Harris

et al. 2013

J Comput Aided Mol Des

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Hepatitis C is a global health problem. While many drug companies have active R&D efforts to develop new drugs for treating Hepatitis C virus (HCV), most target the viral enzymes. The HCV glycoprotein E2 has been shown to play an essential role in hepatocyte invasion by binding to CD81 and other cell surface receptors. This paper describes the use of AutoDock to identify ligand binding sites on the large extracellular loop of the open conformation of CD81 and to perform virtual screening runs to identify sets of small molecule ligands predicted to bind to two of these sites. The best sites selected by AutoLigand were located in regions identified by mutational studies to be the site of E2 binding. Thirty-six ligands predicted by AutoDock to bind to these sites were subsequently tested experimentally to determine if they bound to CD81-LEL. Binding assays conducted using surface Plasmon resonance revealed that 26 out of 36 (72 %) of the ligands bound in vitro to the recombinant CD81-LEL protein. Competition experiments performed using dual polarization interferometry showed that one of the ligands predicted to bind to the large cleft between the C and D helices was also effective in blocking E2 binding to CD81-LEL.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of ligands that target the HCV-E2 binding site on CD81

Olaby

Azzazy

Harris

et al. 2013

J Comput Aided Mol Des

View full text Add to dashboard Cite

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“…An imidazolebased scaffold presenting CD81 helix D amino acid side chains [116] and stapled peptides based on CD81 LEL [117] were designed to antagonize the E2-CD81 interaction by mimicking the putative E2-binding region of CD81. A CLDN1-derived peptide, CL58, was also found to inhibit HCV entry in the post-attachment stage by interacting with HCV E1 and E2 [118].…”

Section: Small Molecules Blocking Viral Glycoproteinsmentioning

confidence: 99%

Strategies to Preclude Hepatitis C Virus Entry

Burnouf¹,

Lin²

2017

Advances in Treatment of Hepatitis C and B

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Without a preventive vaccine, hepatitis C virus (HCV) remains an important pathogen worldwide with millions of carriers at risk of end-stage liver diseases. Despite the introduction of novel direct-acting antivirals (DAAs), resistance problems, challenges with the difficult-to-treat populations and high costs limit the widespread application of these drugs. Antivirals with alternative mechanism(s) of action, such as by restricting viral entry or cell-to-cell spread, could help expand the scope of antiviral strategies for the management of hepatitis C. Transfusion-associated HCV infection remains another issue in endemic and resource-limited areas around the world. This chapter describes some of the latest developments in antiviral strategies to preclude HCV entry, such as through monoclonal antibodies and small molecules, as well as measures to enhance the safety of therapeutic plasma products in blood transfusion.

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“…The choice of the phenyldipyridyl scaffold over the diphenyl, terphenyl, and other scaffolds suggested by Jacoby, 86 Hamilton and coworkers, [87][88][89][90] and others 91 was based on extensive Density Functional Theory analyses of candidate scaffolds ( Figure 10) by Che et al 60 This study provided an understanding for the design of helix mimetics, and why the simple concept of moving the side chains from the interacting surface of a peptide helix to the aromatic scaffold is not straightforward (Figure 11). …”

Section: Combinatorial Library Of Helix Mimeticsmentioning

confidence: 99%

Back to the future: Ribonuclease A

2008

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Pancreatic ribonuclease A (EC 3.1.27.5, RNase) is, perhaps, the best‐studied enzyme of the 20th century. It was isolated by René Dubos, crystallized by Moses Kunitz, sequenced by Stanford Moore and William Stein, and synthesized in the laboratory of Bruce Merrifield, all at the Rockefeller Institute/University. It has proven to be an excellent model system for many different types of experiments, both as an enzyme and as a well‐characterized protein for biophysical studies. Of major significance was the demonstration by Chris Anfinsen at NIH that the primary sequence of RNase encoded the three‐dimensional structure of the enzyme. Many other prominent protein chemists/enzymologists have utilized RNase as a dominant theme in their research. In this review, the history of RNase and its offspring, RNase S (S‐protein/S‐peptide), will be considered, especially the work in the Merrifield group, as a preface to preliminary data and proposed experiments addressing topics of current interest. These include entropy–enthalpy compensation, entropy of ligand binding, the impact of protein modification on thermal stability, and the role of protein dynamics in enzyme action. In continuing to use RNase as a prototypical enzyme, we stand on the shoulders of the giants of protein chemistry to survey the future. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 259–277, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Small molecule inhibition of hepatitis C virus E2 binding to CD81

Cited by 66 publications

References 45 publications

Identification of ligands that target the HCV-E2 binding site on CD81

Identification of ligands that target the HCV-E2 binding site on CD81

Strategies to Preclude Hepatitis C Virus Entry

Back to the future: Ribonuclease A

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