Structure-activity relationships of the Human Immunodeficiency Virus Type 1 maturation inhibitor PF-46396
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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.
Murgatroyd , C , Pirrie , L , Fanny Tran , , 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 , https://doi.org/10.1128/JVI.01075-16
Journal of Virology
Copyright © 2016 Murgatroyd et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
DescriptionThis 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.
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