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Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein.

Al Olaby RR, Cocquerel L, Zemla A, Saas L, Dubuisson J, Vielmetter J, Marcotrigiano J, Khan AG, Vences Catalan F, Perryman AL, Freundlich JS, Forli S, Levy S, Balhorn R, Azzazy HM - PLoS ONE (2014)

Bottom Line: Although several FDA approved drugs targeting the HCV serine protease and polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with interferon and/or ribavirin.Computational docking of a diverse library of 1,715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved amino acid residues involved in the HCV E2: CD81 interaction.Collectively the results obtained with this new structural model of E2c suggest the development of small molecule inhibitors such as 281816 that target E2 and disrupt its interaction with CD81 may provide a new paradigm for HCV treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The American University in Cairo, New Cairo, Egypt.

ABSTRACT
Hepatitis C Virus (HCV) infects 200 million individuals worldwide. Although several FDA approved drugs targeting the HCV serine protease and polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with interferon and/or ribavirin. Recently, two crystal structures of the core of the HCV E2 protein (E2c) have been determined, providing structural information that can now be used to target the E2 protein and develop drugs that disrupt the early stages of HCV infection by blocking E2's interaction with different host factors. Using the E2c structure as a template, we have created a structural model of the E2 protein core (residues 421-645) that contains the three amino acid segments that are not present in either structure. Computational docking of a diverse library of 1,715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved amino acid residues involved in the HCV E2: CD81 interaction. Surface plasmon resonance detection was used to screen the ligand set for binding to recombinant E2 protein, and the best binders were subsequently tested to identify compounds that inhibit the infection of Huh-7 cells by HCV. One compound, 281816, blocked E2 binding to CD81 and inhibited HCV infection in a genotype-independent manner with IC50's ranging from 2.2 µM to 4.6 µM. 281816 blocked the early and late steps of cell-free HCV entry and also abrogated the cell-to-cell transmission of HCV. Collectively the results obtained with this new structural model of E2c suggest the development of small molecule inhibitors such as 281816 that target E2 and disrupt its interaction with CD81 may provide a new paradigm for HCV treatment.

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Relative location of 281816 binding sites 1 and 4 on HCV E2.281816 (structure, top) is predicted to bind to two sites on the E2 protein. Two conformers of 281816 with the lowest free energy of binding are shown bound to site 4. The conformer with the lowest free energy of binding to site 1 is also shown. A video showing the surface structure of the E2 homology model with the three 281816 conformers bound that rotates 360° can be found in Movie S1.
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pone-0111333-g014: Relative location of 281816 binding sites 1 and 4 on HCV E2.281816 (structure, top) is predicted to bind to two sites on the E2 protein. Two conformers of 281816 with the lowest free energy of binding are shown bound to site 4. The conformer with the lowest free energy of binding to site 1 is also shown. A video showing the surface structure of the E2 homology model with the three 281816 conformers bound that rotates 360° can be found in Movie S1.

Mentions: The docking experiments conducted with 281816 identified the two binding sites on E2 shown in Figure 14. One cluster of 281816 conformers bound deep inside a cavity positioned directly above Y618 and P619, two amino acids in site 4 (Figure 3) that are known to contribute to E2’s binding to CD81 [47]. The two strongest 281816 ligand binding modes are shown bound to this site. 281816 was also predicted to bind to a shallow cavity on the opposite side of the protein. These conformers were predicted to bind to site 1 near residues V515, G517, P515 and H421–N423. H421–N423 is part of a larger segment of E2 that has been shown to bind to CD81 [19]. As expected, the ligand positioned above Y618 and P619 in the deeper cavity was predicted to bind more strongly to this region of the protein (free energy of binding of the best bound ligand = −8.64 kcal/mol) than when it was bound to the shallow cavity on the other side of the protein (free energy of binding = −6.39 kcal/mol).


Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein.

Al Olaby RR, Cocquerel L, Zemla A, Saas L, Dubuisson J, Vielmetter J, Marcotrigiano J, Khan AG, Vences Catalan F, Perryman AL, Freundlich JS, Forli S, Levy S, Balhorn R, Azzazy HM - PLoS ONE (2014)

Relative location of 281816 binding sites 1 and 4 on HCV E2.281816 (structure, top) is predicted to bind to two sites on the E2 protein. Two conformers of 281816 with the lowest free energy of binding are shown bound to site 4. The conformer with the lowest free energy of binding to site 1 is also shown. A video showing the surface structure of the E2 homology model with the three 281816 conformers bound that rotates 360° can be found in Movie S1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4214736&req=5

pone-0111333-g014: Relative location of 281816 binding sites 1 and 4 on HCV E2.281816 (structure, top) is predicted to bind to two sites on the E2 protein. Two conformers of 281816 with the lowest free energy of binding are shown bound to site 4. The conformer with the lowest free energy of binding to site 1 is also shown. A video showing the surface structure of the E2 homology model with the three 281816 conformers bound that rotates 360° can be found in Movie S1.
Mentions: The docking experiments conducted with 281816 identified the two binding sites on E2 shown in Figure 14. One cluster of 281816 conformers bound deep inside a cavity positioned directly above Y618 and P619, two amino acids in site 4 (Figure 3) that are known to contribute to E2’s binding to CD81 [47]. The two strongest 281816 ligand binding modes are shown bound to this site. 281816 was also predicted to bind to a shallow cavity on the opposite side of the protein. These conformers were predicted to bind to site 1 near residues V515, G517, P515 and H421–N423. H421–N423 is part of a larger segment of E2 that has been shown to bind to CD81 [19]. As expected, the ligand positioned above Y618 and P619 in the deeper cavity was predicted to bind more strongly to this region of the protein (free energy of binding of the best bound ligand = −8.64 kcal/mol) than when it was bound to the shallow cavity on the other side of the protein (free energy of binding = −6.39 kcal/mol).

Bottom Line: Although several FDA approved drugs targeting the HCV serine protease and polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with interferon and/or ribavirin.Computational docking of a diverse library of 1,715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved amino acid residues involved in the HCV E2: CD81 interaction.Collectively the results obtained with this new structural model of E2c suggest the development of small molecule inhibitors such as 281816 that target E2 and disrupt its interaction with CD81 may provide a new paradigm for HCV treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The American University in Cairo, New Cairo, Egypt.

ABSTRACT
Hepatitis C Virus (HCV) infects 200 million individuals worldwide. Although several FDA approved drugs targeting the HCV serine protease and polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with interferon and/or ribavirin. Recently, two crystal structures of the core of the HCV E2 protein (E2c) have been determined, providing structural information that can now be used to target the E2 protein and develop drugs that disrupt the early stages of HCV infection by blocking E2's interaction with different host factors. Using the E2c structure as a template, we have created a structural model of the E2 protein core (residues 421-645) that contains the three amino acid segments that are not present in either structure. Computational docking of a diverse library of 1,715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved amino acid residues involved in the HCV E2: CD81 interaction. Surface plasmon resonance detection was used to screen the ligand set for binding to recombinant E2 protein, and the best binders were subsequently tested to identify compounds that inhibit the infection of Huh-7 cells by HCV. One compound, 281816, blocked E2 binding to CD81 and inhibited HCV infection in a genotype-independent manner with IC50's ranging from 2.2 µM to 4.6 µM. 281816 blocked the early and late steps of cell-free HCV entry and also abrogated the cell-to-cell transmission of HCV. Collectively the results obtained with this new structural model of E2c suggest the development of small molecule inhibitors such as 281816 that target E2 and disrupt its interaction with CD81 may provide a new paradigm for HCV treatment.

Show MeSH
Related in: MedlinePlus