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Structural Modifications and Biological Evaluations of Rift Valley Fever Virus Inhibitors Identified from Chemical Library Screening
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.ORCID iD: 0000-0002-3253-2736
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2022 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 7, no 8, p. 6854-6868Article in journal (Refereed) Published
Abstract [en]

The Rift Valley fever virus (RVFV) is an emerging high-priority pathogen endemic in Africa with pandemic potential. There is no specific treatment or approved antiviral drugs for the RVFV. We previously developed a cell-based high-throughput assay to screen small molecules targeting the RVFV and identified a potential effective antiviral compound (1-N-(2-(biphenyl-4-yloxy)ethyl)propane-1,3-diamine) as a lead compound. Here, we investigated how structural modifications of the lead compound affected the biological properties and the antiviral effect against the RVFV. We found that the length of the 2-(3-aminopropylamino)ethyl chain of the compound was important for the compound to retain its antiviral activity. The antiviral activity was similar when the 2-(3-aminopropylamino)ethyl chain was replaced with a butyl piperazine chain. However, we could improve the cytotoxicity profile of the lead compound by changing the phenyl piperazine linker from the para-position (compound 9a) to the meta-position (compound 13a). Results from time-of-addition studies suggested that compound 13a might be active during virus post-entry and/or the replication phase of the virus life cycle and seemed to affect the K+ channel. The modifications improved the properties of our lead compound, and our data suggest that 13a is a promising candidate to evaluate further as a therapeutic agent for RVFV infection.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022. Vol. 7, no 8, p. 6854-6868
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-192961DOI: 10.1021/acsomega.1c06513ISI: 000823310600001Scopus ID: 2-s2.0-85125402166OAI: oai:DiVA.org:umu-192961DiVA, id: diva2:1642565
Funder
Swedish Research Council, 2016-06251Familjen Erling-Perssons StiftelseRegion VästerbottenAvailable from: 2022-03-07 Created: 2022-03-07 Last updated: 2024-07-02Bibliographically approved

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Islam, KoushikulCarlsson, MarcusEnquist, Per-AndersQian, WeixingMarttila, MarkoStrand, MårtenAhlm, ClasEvander, Magnus

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Islam, KoushikulCarlsson, MarcusEnquist, Per-AndersQian, WeixingMarttila, MarkoStrand, MårtenAhlm, ClasEvander, Magnus
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Department of Clinical MicrobiologyDepartment of Chemistry
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Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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CiteExportLink to record
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