Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry
Broadly neutralizing antibodies (bNAbs) are potent in neutralizing a wide range of HIV strains. VRC01 is a CD4-binding-site (CD4-bs) class of bNAbs that binds to the conserved CD4-binding region of HIV-1 envelope (env) protein. Natural products that mimic VRC01 bNAbs by interacting with the conserve...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/2/474 |
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| author | Nneka Ugwu-Korie Osbourne Quaye Edward Wright Sylvester Languon Odame Agyapong Emmanuel Broni Yash Gupta Prakasha Kempaiah Samuel K. Kwofie |
| author_facet | Nneka Ugwu-Korie Osbourne Quaye Edward Wright Sylvester Languon Odame Agyapong Emmanuel Broni Yash Gupta Prakasha Kempaiah Samuel K. Kwofie |
| author_sort | Nneka Ugwu-Korie |
| collection | DOAJ |
| description | Broadly neutralizing antibodies (bNAbs) are potent in neutralizing a wide range of HIV strains. VRC01 is a CD4-binding-site (CD4-bs) class of bNAbs that binds to the conserved CD4-binding region of HIV-1 envelope (env) protein. Natural products that mimic VRC01 bNAbs by interacting with the conserved CD4-binding regions may serve as a new generation of HIV-1 entry inhibitors by being broadly reactive and potently neutralizing. This study aimed to identify compounds that mimic VRC01 by interacting with the CD4-bs of HIV-1 gp120 and thereby inhibiting viral entry into target cells. Libraries of purchasable natural products were virtually screened against clade A/E recombinant 93TH057 (PDB: 3NGB) and clade B (PDB ID: 3J70) HIV-1 env protein. Protein–ligand interaction profiling from molecular docking and dynamics simulations showed that the compounds had intermolecular hydrogen and hydrophobic interactions with conserved amino acid residues on the CD4-binding site of recombinant clade A/E and clade B HIV-1 gp120. Four potential lead compounds, NP-005114, NP-008297, NP-007422, and NP-007382, were used for cell-based antiviral infectivity inhibition assay using clade B (HXB2) env pseudotype virus (PV). The four compounds inhibited the entry of HIV HXB2 pseudotype viruses into target cells at 50% inhibitory concentrations (IC<sub>50</sub>) of 15.2 µM (9.7 µg/mL), 10.1 µM (7.5 µg/mL), 16.2 µM (12.7 µg/mL), and 21.6 µM (12.9 µg/mL), respectively. The interaction of these compounds with critical residues of the CD4-binding site of more than one clade of HIV gp120 and inhibition of HIV-1 entry into the target cell demonstrate the possibility of a new class of HIV entry inhibitors. |
| first_indexed | 2024-03-09T11:36:55Z |
| format | Article |
| id | doaj.art-54c299fa218b4cbeae41fef4fbceed89 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T11:36:55Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-54c299fa218b4cbeae41fef4fbceed892023-11-30T23:40:22ZengMDPI AGMolecules1420-30492023-01-0128247410.3390/molecules28020474Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 EntryNneka Ugwu-Korie0Osbourne Quaye1Edward Wright2Sylvester Languon3Odame Agyapong4Emmanuel Broni5Yash Gupta6Prakasha Kempaiah7Samuel K. Kwofie8West African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, GhanaWest African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, GhanaSchool of Life Sciences, University of Sussex, Brighton BN1 9QG, UKWest African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, GhanaDepartment of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, GhanaDepartment of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, GhanaInfectious Diseases, Mayo Clinic, Jacksonville, FL 32224, USAInfectious Diseases, Mayo Clinic, Jacksonville, FL 32224, USAWest African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, GhanaBroadly neutralizing antibodies (bNAbs) are potent in neutralizing a wide range of HIV strains. VRC01 is a CD4-binding-site (CD4-bs) class of bNAbs that binds to the conserved CD4-binding region of HIV-1 envelope (env) protein. Natural products that mimic VRC01 bNAbs by interacting with the conserved CD4-binding regions may serve as a new generation of HIV-1 entry inhibitors by being broadly reactive and potently neutralizing. This study aimed to identify compounds that mimic VRC01 by interacting with the CD4-bs of HIV-1 gp120 and thereby inhibiting viral entry into target cells. Libraries of purchasable natural products were virtually screened against clade A/E recombinant 93TH057 (PDB: 3NGB) and clade B (PDB ID: 3J70) HIV-1 env protein. Protein–ligand interaction profiling from molecular docking and dynamics simulations showed that the compounds had intermolecular hydrogen and hydrophobic interactions with conserved amino acid residues on the CD4-binding site of recombinant clade A/E and clade B HIV-1 gp120. Four potential lead compounds, NP-005114, NP-008297, NP-007422, and NP-007382, were used for cell-based antiviral infectivity inhibition assay using clade B (HXB2) env pseudotype virus (PV). The four compounds inhibited the entry of HIV HXB2 pseudotype viruses into target cells at 50% inhibitory concentrations (IC<sub>50</sub>) of 15.2 µM (9.7 µg/mL), 10.1 µM (7.5 µg/mL), 16.2 µM (12.7 µg/mL), and 21.6 µM (12.9 µg/mL), respectively. The interaction of these compounds with critical residues of the CD4-binding site of more than one clade of HIV gp120 and inhibition of HIV-1 entry into the target cell demonstrate the possibility of a new class of HIV entry inhibitors.https://www.mdpi.com/1420-3049/28/2/474HIV-1 entryinhibitionCD4-binding siteVRC01gp120virtual screening |
| spellingShingle | Nneka Ugwu-Korie Osbourne Quaye Edward Wright Sylvester Languon Odame Agyapong Emmanuel Broni Yash Gupta Prakasha Kempaiah Samuel K. Kwofie Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry Molecules HIV-1 entry inhibition CD4-binding site VRC01 gp120 virtual screening |
| title | Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry |
| title_full | Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry |
| title_fullStr | Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry |
| title_full_unstemmed | Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry |
| title_short | Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry |
| title_sort | structure based identification of natural product derived compounds with potential to inhibit hiv 1 entry |
| topic | HIV-1 entry inhibition CD4-binding site VRC01 gp120 virtual screening |
| url | https://www.mdpi.com/1420-3049/28/2/474 |
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