Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses
Lassa fever (LF), a viral hemorrhagic fever disease with a case fatality rate that can be over 20% among hospitalized LF patients, is endemic to many West African countries. Currently, no vaccines or therapies are specifically licensed to prevent or treat LF, hence the significance of developing the...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/17/1/117 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832587286244491264 |
|---|---|
| author | Chukwudi A. Ofodile Ikemefuna C. Uzochukwu Fortunatus C. Ezebuo InnocentMary Ejiofor Mercy Adebola Innocent Okpoli Beatrice Cubitt Haydar Witwit Chetachi B. Okwuanaso Ngozi Onyemelukwe Juan Carlos de la Torre |
| author_facet | Chukwudi A. Ofodile Ikemefuna C. Uzochukwu Fortunatus C. Ezebuo InnocentMary Ejiofor Mercy Adebola Innocent Okpoli Beatrice Cubitt Haydar Witwit Chetachi B. Okwuanaso Ngozi Onyemelukwe Juan Carlos de la Torre |
| author_sort | Chukwudi A. Ofodile |
| collection | DOAJ |
| description | Lassa fever (LF), a viral hemorrhagic fever disease with a case fatality rate that can be over 20% among hospitalized LF patients, is endemic to many West African countries. Currently, no vaccines or therapies are specifically licensed to prevent or treat LF, hence the significance of developing therapeutics against the mammarenavirus Lassa virus (LASV), the causative agent of LF. We used in silico docking approaches to investigate the binding affinities of 2015 existing drugs to LASV proteins known to play critical roles in the formation and activity of the virus ribonucleoprotein complex (vRNP) responsible for directing replication and transcription of the viral genome. Validation of docking protocols were achieved with reference inhibitors of the respective targets. Our in silico docking screen identified five drugs (dexamethasone, tadalafil, mefloquine, ergocalciferol, and flunarizine) with strong predicted binding affinity to LASV proteins involved in the formation of the vRNP. We used cell-based functional assays to evaluate the antiviral activity of the five selected drugs. We found that flunarizine, a calcium-entry blocker, inhibited the vRNP activity of LASV and LCMV and virus surface glycoprotein fusion activity required for mammarenavirus cell entry. Consistently with these findings, flunarizine significantly reduced peak titers of LCMV in a multi-step growth kinetics assay in human A549 cells. Flunarizine is being used in several countries worldwide to treat vertigo and migraine, supporting the interest in exploring its repurposing as a candidate drug to treat LASV infections. |
| format | Article |
| id | doaj-art-5d264c824dc74fff965490ed9d9d0eb5 |
| institution | Kabale University |
| issn | 1999-4915 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj-art-5d264c824dc74fff965490ed9d9d0eb52025-01-24T13:52:39ZengMDPI AGViruses1999-49152025-01-0117111710.3390/v17010117Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic MammarenavirusesChukwudi A. Ofodile0Ikemefuna C. Uzochukwu1Fortunatus C. Ezebuo2InnocentMary Ejiofor3Mercy Adebola4Innocent Okpoli5Beatrice Cubitt6Haydar Witwit7Chetachi B. Okwuanaso8Ngozi Onyemelukwe9Juan Carlos de la Torre10Department of Medical Laboratory Science, Faculty of Health Sciences and Technology, Nnamdi Azikiwe University, Awka 420218, Anambra, NigeriaDepartment of Pharmaceutical & Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Awka 420218, Anambra, NigeriaDepartment of Pharmaceutical & Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Awka 420218, Anambra, NigeriaDepartment of Pharmacognosy & Traditional Medicine, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Awka 420218, Anambra, NigeriaDepartment of Pharmaceutical & Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Awka 420218, Anambra, NigeriaDepartment of Pharmaceutical & Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Awka 420218, Anambra, NigeriaDepartment of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USADepartment of Medical Laboratory Science, Faculty of Health Sciences and Technology, Nnamdi Azikiwe University, Awka 420218, Anambra, NigeriaDepartment of Medical Laboratory Sciences, Faculty of Health Sciences and Technology, University of Nigeria, Nsukka 401105, Enugu, NigeriaDepartment of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USALassa fever (LF), a viral hemorrhagic fever disease with a case fatality rate that can be over 20% among hospitalized LF patients, is endemic to many West African countries. Currently, no vaccines or therapies are specifically licensed to prevent or treat LF, hence the significance of developing therapeutics against the mammarenavirus Lassa virus (LASV), the causative agent of LF. We used in silico docking approaches to investigate the binding affinities of 2015 existing drugs to LASV proteins known to play critical roles in the formation and activity of the virus ribonucleoprotein complex (vRNP) responsible for directing replication and transcription of the viral genome. Validation of docking protocols were achieved with reference inhibitors of the respective targets. Our in silico docking screen identified five drugs (dexamethasone, tadalafil, mefloquine, ergocalciferol, and flunarizine) with strong predicted binding affinity to LASV proteins involved in the formation of the vRNP. We used cell-based functional assays to evaluate the antiviral activity of the five selected drugs. We found that flunarizine, a calcium-entry blocker, inhibited the vRNP activity of LASV and LCMV and virus surface glycoprotein fusion activity required for mammarenavirus cell entry. Consistently with these findings, flunarizine significantly reduced peak titers of LCMV in a multi-step growth kinetics assay in human A549 cells. Flunarizine is being used in several countries worldwide to treat vertigo and migraine, supporting the interest in exploring its repurposing as a candidate drug to treat LASV infections.https://www.mdpi.com/1999-4915/17/1/117Lassa virusLCMVminigenomein silico dockingflunarizineantiviral |
| spellingShingle | Chukwudi A. Ofodile Ikemefuna C. Uzochukwu Fortunatus C. Ezebuo InnocentMary Ejiofor Mercy Adebola Innocent Okpoli Beatrice Cubitt Haydar Witwit Chetachi B. Okwuanaso Ngozi Onyemelukwe Juan Carlos de la Torre Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses Viruses Lassa virus LCMV minigenome in silico docking flunarizine antiviral |
| title | Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses |
| title_full | Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses |
| title_fullStr | Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses |
| title_full_unstemmed | Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses |
| title_short | Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses |
| title_sort | flunarizine as a candidate for drug repurposing against human pathogenic mammarenaviruses |
| topic | Lassa virus LCMV minigenome in silico docking flunarizine antiviral |
| url | https://www.mdpi.com/1999-4915/17/1/117 |
| work_keys_str_mv | AT chukwudiaofodile flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT ikemefunacuzochukwu flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT fortunatuscezebuo flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT innocentmaryejiofor flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT mercyadebola flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT innocentokpoli flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT beatricecubitt flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT haydarwitwit flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT chetachibokwuanaso flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT ngozionyemelukwe flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses AT juancarlosdelatorre flunarizineasacandidatefordrugrepurposingagainsthumanpathogenicmammarenaviruses |