Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81
Aim: Harzianoic acids A and B (Hz-A/B) are two rare cyclobutene-containing sesquiterpenes isolated from a marine strain of the sponge-associated fungus Trichoderma harzianum. They display anticancer and antiviral effects, reducing the entry of hepatitis C virus (HCV) into hepatocarcinoma cells. The...
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Open Exploration
2023-11-01
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| Online Access: | https://www.explorationpub.com/uploads/Article/A100827/100827.pdf |
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| author | Gérard Vergoten Christian Bailly |
| author_facet | Gérard Vergoten Christian Bailly |
| author_sort | Gérard Vergoten |
| collection | DOAJ |
| description | Aim: Harzianoic acids A and B (Hz-A/B) are two rare cyclobutene-containing sesquiterpenes isolated from a marine strain of the sponge-associated fungus Trichoderma harzianum. They display anticancer and antiviral effects, reducing the entry of hepatitis C virus (HCV) into hepatocarcinoma cells. The large extracellular loop (LEL) of the tetraspanin protein CD81 represents a molecular target for both Hz-A and Hz-B. Methods: The interaction of Hz-A/B with CD81 has been modeled, using structures of the cholesterol-bound full-length protein and a truncated protein corresponding to the LEL portion. The models mimicked the closed and open conformations of the LEL. Results: The best ligand Hz-B can form stable complexes with the open LEL structure, whereas binding to the closed form is drastically reduced. Key H-bonds between the acid groups of Hz-B and the CD81-LEL domain stabilize the ligand-protein complex. A comparison of the interaction with the homologous tetraspanin CD9, which also presents a dynamic open/closed equilibrium, underlined the marked selectivity of Hz-A/B for CD81 over CD9. The cyclobutane-containing monoterpene grandisol, an insect pheromone, has been identified as a fragment that could be modulated to improve its modest interaction with CD81-LEL. Conclusions: The modeling docking analysis suggests that Hz-B is a robust CD81 binder, better interacting with the LEL portion of CD81 compared to CD9-LEL. The docking study paves the way to the design of small molecules targeting CD81. The study has implications for a better understanding of CD81 binding properties and the regulation of its activities. |
| format | Article |
| id | doaj-art-bf9665bccc77487e9bab75edb01c7149 |
| institution | Kabale University |
| issn | 2836-7677 |
| language | English |
| publishDate | 2023-11-01 |
| publisher | Open Exploration |
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| series | Exploration of Drug Science |
| spelling | doaj-art-bf9665bccc77487e9bab75edb01c71492025-02-08T03:44:56ZengOpen ExplorationExploration of Drug Science2836-76772023-11-011640541910.37349/eds.2023.00027Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81Gérard Vergoten0https://orcid.org/0000-0001-6336-3923Christian Bailly1https://orcid.org/0000-0002-2973-9357Univ. Lille, Inserm, U1286 – INFINITE – Lille Inflammation Research International Center, ICPAL, 59000 Lille, FranceUniv. Lille, CHU Lille, CNRS, Inserm, UMR9020 – UMR1277 – Canther – Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France; Oncowitan, Scientific Consulting Office, 59290 Lille, FranceAim: Harzianoic acids A and B (Hz-A/B) are two rare cyclobutene-containing sesquiterpenes isolated from a marine strain of the sponge-associated fungus Trichoderma harzianum. They display anticancer and antiviral effects, reducing the entry of hepatitis C virus (HCV) into hepatocarcinoma cells. The large extracellular loop (LEL) of the tetraspanin protein CD81 represents a molecular target for both Hz-A and Hz-B. Methods: The interaction of Hz-A/B with CD81 has been modeled, using structures of the cholesterol-bound full-length protein and a truncated protein corresponding to the LEL portion. The models mimicked the closed and open conformations of the LEL. Results: The best ligand Hz-B can form stable complexes with the open LEL structure, whereas binding to the closed form is drastically reduced. Key H-bonds between the acid groups of Hz-B and the CD81-LEL domain stabilize the ligand-protein complex. A comparison of the interaction with the homologous tetraspanin CD9, which also presents a dynamic open/closed equilibrium, underlined the marked selectivity of Hz-A/B for CD81 over CD9. The cyclobutane-containing monoterpene grandisol, an insect pheromone, has been identified as a fragment that could be modulated to improve its modest interaction with CD81-LEL. Conclusions: The modeling docking analysis suggests that Hz-B is a robust CD81 binder, better interacting with the LEL portion of CD81 compared to CD9-LEL. The docking study paves the way to the design of small molecules targeting CD81. The study has implications for a better understanding of CD81 binding properties and the regulation of its activities.https://www.explorationpub.com/uploads/Article/A100827/100827.pdftetraspanincd81cd9harzianoic acidmolecular modelinggrandisol |
| spellingShingle | Gérard Vergoten Christian Bailly Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81 Exploration of Drug Science tetraspanin cd81 cd9 harzianoic acid molecular modeling grandisol |
| title | Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81 |
| title_full | Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81 |
| title_fullStr | Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81 |
| title_full_unstemmed | Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81 |
| title_short | Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81 |
| title_sort | insights into the binding selectivity of harzianoic acids a and b to tetraspanin cd81 |
| topic | tetraspanin cd81 cd9 harzianoic acid molecular modeling grandisol |
| url | https://www.explorationpub.com/uploads/Article/A100827/100827.pdf |
| work_keys_str_mv | AT gerardvergoten insightsintothebindingselectivityofharzianoicacidsaandbtotetraspanincd81 AT christianbailly insightsintothebindingselectivityofharzianoicacidsaandbtotetraspanincd81 |