In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2
We have previously published research on the anti-viral properties of an alkaloid mixture extracted from <i>Nuphar lutea</i>, the major components of the partially purified mixture found by NMR analysis. These are mostly dimeric sesquiterpene thioalkaloids called thiobinupharidines and t...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/9/8327 |
| _version_ | 1797602388038647808 |
|---|---|
| author | Shay Weiss Kamran Waidha Saravanakumar Rajendran Daniel Benharroch Jannat Khalilia Haim Levy Elad Bar-David Avi Golan-Goldhirsh Jacob Gopas Amir Ben-Shmuel |
| author_facet | Shay Weiss Kamran Waidha Saravanakumar Rajendran Daniel Benharroch Jannat Khalilia Haim Levy Elad Bar-David Avi Golan-Goldhirsh Jacob Gopas Amir Ben-Shmuel |
| author_sort | Shay Weiss |
| collection | DOAJ |
| description | We have previously published research on the anti-viral properties of an alkaloid mixture extracted from <i>Nuphar lutea</i>, the major components of the partially purified mixture found by NMR analysis. These are mostly dimeric sesquiterpene thioalkaloids called thiobinupharidines and thiobinuphlutidines against the negative strand RNA measles virus (MV). We have previously reported that this extract inhibits the MV as well as its ability to downregulate several MV proteins in persistently MV-infected cells, especially the P (phospho)-protein. Based on our observation that the <i>Nuphar</i> extract is effective in vitro against the MV, and the immediate need that the coronavirus disease 2019 (COVID-19) pandemic created, we tested here the ability of 6,6′-dihydroxythiobinupharidine DTBN, an active small molecule, isolated from the <i>Nuphar lutea</i> extract, on COVID-19. As shown here, DTBN effectively inhibits SARS-CoV-2 production in Vero E6 cells at non-cytotoxic concentrations. The short-term daily administration of DTBN to infected mice delayed the occurrence of severe clinical outcomes, lowered virus levels in the lungs and improved survival with minimal changes in lung histology. The viral load on lungs was significantly reduced in the treated mice. DTBN is a pleiotropic small molecule with multiple targets. Its anti-inflammatory properties affect a variety of pathogens including SARS-CoV-2 as shown here. Its activity appears to target both pathogen specific (as suggested by docking analysis) as well as cellular proteins, such as NF-κB, PKCs, cathepsins and topoisomerase 2, that we have previously identified in our work. Thus, this combined double action of virus inhibition and anti-inflammatory activity may enhance the overall effectivity of DTBN. The promising results from this proof-of-concept in vitro and in vivo preclinical study should encourage future studies to optimize the use of DTBN and/or its molecular derivatives against this and other related viruses. |
| first_indexed | 2024-03-11T04:16:21Z |
| format | Article |
| id | doaj.art-9d5c4d36c38a458d9fe235059cc97573 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:16:21Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9d5c4d36c38a458d9fe235059cc975732023-11-17T23:08:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249832710.3390/ijms24098327In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2Shay Weiss0Kamran Waidha1Saravanakumar Rajendran2Daniel Benharroch3Jannat Khalilia4Haim Levy5Elad Bar-David6Avi Golan-Goldhirsh7Jacob Gopas8Amir Ben-Shmuel9Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 7410001, IsraelThe Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, IsraelChemistry Division, SAS, Vellore Institute of Technology, Chennai Campus, Chennai 600127, IndiaDepartment of Pathology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, IsraelThe Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, IsraelDepartment of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 7410001, IsraelDepartment of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 7410001, IsraelThe Jacob Blaustein Institutes for Desert Research (BIDR), Ben-Gurion University of the Negev, Sede Boqer Campus, Sde Boker 8410501, IsraelThe Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, IsraelDepartment of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 7410001, IsraelWe have previously published research on the anti-viral properties of an alkaloid mixture extracted from <i>Nuphar lutea</i>, the major components of the partially purified mixture found by NMR analysis. These are mostly dimeric sesquiterpene thioalkaloids called thiobinupharidines and thiobinuphlutidines against the negative strand RNA measles virus (MV). We have previously reported that this extract inhibits the MV as well as its ability to downregulate several MV proteins in persistently MV-infected cells, especially the P (phospho)-protein. Based on our observation that the <i>Nuphar</i> extract is effective in vitro against the MV, and the immediate need that the coronavirus disease 2019 (COVID-19) pandemic created, we tested here the ability of 6,6′-dihydroxythiobinupharidine DTBN, an active small molecule, isolated from the <i>Nuphar lutea</i> extract, on COVID-19. As shown here, DTBN effectively inhibits SARS-CoV-2 production in Vero E6 cells at non-cytotoxic concentrations. The short-term daily administration of DTBN to infected mice delayed the occurrence of severe clinical outcomes, lowered virus levels in the lungs and improved survival with minimal changes in lung histology. The viral load on lungs was significantly reduced in the treated mice. DTBN is a pleiotropic small molecule with multiple targets. Its anti-inflammatory properties affect a variety of pathogens including SARS-CoV-2 as shown here. Its activity appears to target both pathogen specific (as suggested by docking analysis) as well as cellular proteins, such as NF-κB, PKCs, cathepsins and topoisomerase 2, that we have previously identified in our work. Thus, this combined double action of virus inhibition and anti-inflammatory activity may enhance the overall effectivity of DTBN. The promising results from this proof-of-concept in vitro and in vivo preclinical study should encourage future studies to optimize the use of DTBN and/or its molecular derivatives against this and other related viruses.https://www.mdpi.com/1422-0067/24/9/8327SARS-CoV-2COVID-196,6′-dihydroxythiobinupharidine (DTBN)RNA-dependent RNA polymerase (RdRp)anti-viral small molecule drug |
| spellingShingle | Shay Weiss Kamran Waidha Saravanakumar Rajendran Daniel Benharroch Jannat Khalilia Haim Levy Elad Bar-David Avi Golan-Goldhirsh Jacob Gopas Amir Ben-Shmuel In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2 International Journal of Molecular Sciences SARS-CoV-2 COVID-19 6,6′-dihydroxythiobinupharidine (DTBN) RNA-dependent RNA polymerase (RdRp) anti-viral small molecule drug |
| title | In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2 |
| title_full | In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2 |
| title_fullStr | In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2 |
| title_full_unstemmed | In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2 |
| title_short | In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from <i>Nuphar lutea</i> on Cells and K18-<i>hACE2</i> Mice Infected with SARS-CoV-2 |
| title_sort | in vitro and in vivo therapeutic potential of 6 6 dihydroxythiobinupharidine dtbn from i nuphar lutea i on cells and k18 i hace2 i mice infected with sars cov 2 |
| topic | SARS-CoV-2 COVID-19 6,6′-dihydroxythiobinupharidine (DTBN) RNA-dependent RNA polymerase (RdRp) anti-viral small molecule drug |
| url | https://www.mdpi.com/1422-0067/24/9/8327 |
| work_keys_str_mv | AT shayweiss invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT kamranwaidha invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT saravanakumarrajendran invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT danielbenharroch invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT jannatkhalilia invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT haimlevy invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT eladbardavid invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT avigolangoldhirsh invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT jacobgopas invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 AT amirbenshmuel invitroandinvivotherapeuticpotentialof66dihydroxythiobinupharidinedtbnfrominupharluteaioncellsandk18ihace2imiceinfectedwithsarscov2 |