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Structure-activity relationships of the Human Immunodeficiency Virus type 1 maturation inhibitor PF-46396
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dc.contributor.author | Murgatroyd, Christopher | |
dc.contributor.author | Pirrie, Lisa | |
dc.contributor.author | Tran, Fanny | |
dc.contributor.author | Smith, Terry K. | |
dc.contributor.author | Westwood, Nicholas J. | |
dc.contributor.author | Adamson, Catherine S. | |
dc.date.accessioned | 2016-08-29T14:30:45Z | |
dc.date.available | 2016-08-29T14:30:45Z | |
dc.date.issued | 2016-09 | |
dc.identifier | 243686503 | |
dc.identifier | c08634b2-71b0-470f-9a25-18dee3fc9b87 | |
dc.identifier | 000382314100014 | |
dc.identifier | 84984653332 | |
dc.identifier | 000382314100014 | |
dc.identifier.citation | Murgatroyd , C , Pirrie , L , Tran , F , Smith , T K , Westwood , N J & Adamson , C S 2016 , ' Structure-activity relationships of the Human Immunodeficiency Virus type 1 maturation inhibitor PF-46396 ' , Journal of Virology , vol. 90 , no. 18 , pp. 8181-8197 . https://doi.org/10.1128/JVI.01075-16 | en |
dc.identifier.issn | 0022-538X | |
dc.identifier.other | ORCID: /0000-0003-0630-0138/work/56424159 | |
dc.identifier.other | ORCID: /0000-0001-7673-5212/work/60630451 | |
dc.identifier.uri | https://hdl.handle.net/10023/9394 | |
dc.description | This work was funded by the University of St Andrews and Society for Applied Microbiology New Lecturer Research Grant awarded to CSA, Wellcome Trust grant (093228) awarded to TKS. | en |
dc.description.abstract | HIV-1 maturation inhibitors are a novel class of antiretroviral compounds, which consist of two structurally distinct chemical classes; betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by a similar mode of action to generate aberrant non-infectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study we utilized a series of novel analogues, with decreasing similarity to PF-46396, to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into WT immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity, but not an absolute requirement for Gag binding, (ii) the trifluromethyl group is optimal but not essential for antiviral activity and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but not essential as its replacement is tolerated. | |
dc.format.extent | 17 | |
dc.format.extent | 2993943 | |
dc.language.iso | eng | |
dc.relation.ispartof | Journal of Virology | en |
dc.subject | QR355 Virology | en |
dc.subject | BDC | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject.lcc | QR355 | en |
dc.title | Structure-activity relationships of the Human Immunodeficiency Virus type 1 maturation inhibitor PF-46396 | en |
dc.type | Journal article | en |
dc.contributor.sponsor | The Wellcome Trust | en |
dc.contributor.institution | University of St Andrews. School of Biology | en |
dc.contributor.institution | University of St Andrews. School of Chemistry | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.contributor.institution | University of St Andrews. EaSTCHEM | en |
dc.identifier.doi | https://doi.org/10.1128/JVI.01075-16 | |
dc.description.status | Peer reviewed | en |
dc.date.embargoedUntil | 2016-08-26 | |
dc.identifier.grantnumber | 093228/Z/10/Z | en |
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