Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases
Several neurotropic viruses are members of the flavivirus and alphavirus families. Infections caused by these viruses may cause long-term neurological sequelae in humans. The continuous emergence of infections caused by viruses around the world, such as the chikungunya virus (CHIKV) (Alphavirus genu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/10/7/1331 |
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| author | Raphael J. Eberle Danilo S. Olivier Marcos S. Amaral Carolina C. Pacca Mauricio L. Nogueira Raghuvir K. Arni Dieter Willbold Monika A. Coronado |
| author_facet | Raphael J. Eberle Danilo S. Olivier Marcos S. Amaral Carolina C. Pacca Mauricio L. Nogueira Raghuvir K. Arni Dieter Willbold Monika A. Coronado |
| author_sort | Raphael J. Eberle |
| collection | DOAJ |
| description | Several neurotropic viruses are members of the flavivirus and alphavirus families. Infections caused by these viruses may cause long-term neurological sequelae in humans. The continuous emergence of infections caused by viruses around the world, such as the chikungunya virus (CHIKV) (Alphavirus genus), the zika virus (ZIKV) and the yellow fever virus (YFV) (both of the Flavivirus genus), warrants the development of new strategies to combat them. Our study demonstrates the inhibitory potential of the water-soluble vitamin riboflavin against NS2B/NS3<sup>pro</sup> of ZIKV and YFV and nsP2<sup>pro</sup> of CHIKV. Riboflavin presents a competitive inhibition mode with IC<sub>50</sub> values in the medium µM range of 79.4 ± 5.0 µM for ZIKV NS2B/NS3<sup>pro</sup> and 45.7 ± 2.9 μM for YFV NS2B/NS3<sup>pro</sup>. Against CHIKV nsP2<sup>pro</sup>, the vitamin showed a very strong effect (93 ± 5.7 nM). The determined dissociation constants (K<sub>D</sub>) are significantly below the threshold value of 30 µM. The ligand binding increases the thermal stability between 4 °C and 8 °C. Unexpectedly, riboflavin showed inhibiting activity against another viral protein; the molecule was also able to inhibit the viral entry of CHIKV. Molecular dynamics simulations indicated great stability of riboflavin in the protease active site, which validates the repurposing of riboflavin as a promising molecule in drug development against the viruses presented here. |
| first_indexed | 2024-03-09T10:14:42Z |
| format | Article |
| id | doaj.art-c07d0c47bf564a379d01e6dc6fba942e |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-09T10:14:42Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-c07d0c47bf564a379d01e6dc6fba942e2023-12-01T22:28:17ZengMDPI AGMicroorganisms2076-26072022-06-01107133110.3390/microorganisms10071331Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus ProteasesRaphael J. Eberle0Danilo S. Olivier1Marcos S. Amaral2Carolina C. Pacca3Mauricio L. Nogueira4Raghuvir K. Arni5Dieter Willbold6Monika A. Coronado7Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, 52428 Jülich, GermanyCenter of Integrated Sciences, Campus Cimba, Federal University of Tocantins, Araguaína 77824-838, TO, BrazilInstitute of Physics, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, MS, BrazilInstituto Superior de Educação Ceres, FACERES Medical School, São José do Rio Preto 15090-305, SP, BrazilLaboratório de Pesquisas em Virologia, Departamento de Doenças Dermatológicas, Infecciosas e Parasitárias, Faculdade de Medicina de São José do Rio Preto-FAMERP, São José do Rio Preto 15090-000, SP, BrazilMultiuser Center for Biomolecular Innovation, Department of Physics, IBILCE, São Paulo State University, São Jose do Rio Preto 15054-000, SP, BrazilInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, 52428 Jülich, GermanyInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, 52428 Jülich, GermanySeveral neurotropic viruses are members of the flavivirus and alphavirus families. Infections caused by these viruses may cause long-term neurological sequelae in humans. The continuous emergence of infections caused by viruses around the world, such as the chikungunya virus (CHIKV) (Alphavirus genus), the zika virus (ZIKV) and the yellow fever virus (YFV) (both of the Flavivirus genus), warrants the development of new strategies to combat them. Our study demonstrates the inhibitory potential of the water-soluble vitamin riboflavin against NS2B/NS3<sup>pro</sup> of ZIKV and YFV and nsP2<sup>pro</sup> of CHIKV. Riboflavin presents a competitive inhibition mode with IC<sub>50</sub> values in the medium µM range of 79.4 ± 5.0 µM for ZIKV NS2B/NS3<sup>pro</sup> and 45.7 ± 2.9 μM for YFV NS2B/NS3<sup>pro</sup>. Against CHIKV nsP2<sup>pro</sup>, the vitamin showed a very strong effect (93 ± 5.7 nM). The determined dissociation constants (K<sub>D</sub>) are significantly below the threshold value of 30 µM. The ligand binding increases the thermal stability between 4 °C and 8 °C. Unexpectedly, riboflavin showed inhibiting activity against another viral protein; the molecule was also able to inhibit the viral entry of CHIKV. Molecular dynamics simulations indicated great stability of riboflavin in the protease active site, which validates the repurposing of riboflavin as a promising molecule in drug development against the viruses presented here.https://www.mdpi.com/2076-2607/10/7/1331alphavirusflavivirusNS2B/NS3<sup>pro</sup>nsP2<sup>pro</sup>riboflavincompetitive inhibitor |
| spellingShingle | Raphael J. Eberle Danilo S. Olivier Marcos S. Amaral Carolina C. Pacca Mauricio L. Nogueira Raghuvir K. Arni Dieter Willbold Monika A. Coronado Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases Microorganisms alphavirus flavivirus NS2B/NS3<sup>pro</sup> nsP2<sup>pro</sup> riboflavin competitive inhibitor |
| title | Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases |
| title_full | Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases |
| title_fullStr | Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases |
| title_full_unstemmed | Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases |
| title_short | Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases |
| title_sort | riboflavin a potent neuroprotective vitamin focus on flavivirus and alphavirus proteases |
| topic | alphavirus flavivirus NS2B/NS3<sup>pro</sup> nsP2<sup>pro</sup> riboflavin competitive inhibitor |
| url | https://www.mdpi.com/2076-2607/10/7/1331 |
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