Skip to content

Research at St Andrews

Structure-activity relationships of the Human Immunodeficiency Virus Type 1 maturation inhibitor PF-46396

Research output: Research - peer-reviewArticle

DOI

Open Access permissions

Open

Author(s)

Christopher Murgatroyd, Lisa Pirrie, Fanny Tran, Terry K. Smith, Nicholas J. Westwood, Catherine S. Adamson

School/Research organisations

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.
Close

Details

Original languageEnglish
Pages (from-to)8181-8197
Number of pages17
JournalJournal of Virology
Volume90
Issue number18
Early online date6 Jul 2016
DOIs
StatePublished - Sep 2016

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Derivatisable cyanobactin analogues: a semisynthetic approach

    Oueis, E., Adamson, C. S., Mann, G., Ludewig, H., Naismith, J., Redpath, P., Migaud, M., Westwood, N. J. & Naismith, J. 14 Dec 2015 In : ChemBioChem. 16, 18, p. 2646-2650

    Research output: Research - peer-reviewArticle

  2. A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro

    Zhou, L., Stewart, G., Rideau, E., Westwood, N. J. & Smith, T. K. 14 Feb 2013 In : Journal of Medicinal Chemistry. 56, 3, p. 796–806 11 p.

    Research output: Research - peer-reviewArticle

  3. Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice

    Vasou, A., Paulus, C., Narloch, J., Gage, Z. O., Rameix-Welti, M-A., Eléouët, J-F., Nevels, M., Randall, R. E. & Adamson, C. S. Feb 2018 In : Antiviral Research. 150, p. 79-92

    Research output: Research - peer-reviewArticle

  4. Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease

    Gaspar, L., Coron, R. P., Kongthoo Lin, P., Costa, D. M., Perez-Cabezas, B., Tavares, J., Roura-Ferrer, M., Ramos, I., Ronin, C., Major, L. L., Ciesielski, F., Pemberton, I. K., MacDougall, J., Ciapetti, P., Smith, T. K. & Cordeiro-da-Silva, A. 22 Jan 2018 In : PLoS Neglected Tropical Diseases. 12, 1, 30 p., e0006180

    Research output: Research - peer-reviewArticle

Related by journal

  1. Association of human papillomavirus 16 E2 with Rad50-interacting protein 1 enhances viral DNA replication

    Campos-León, K., Wijendra, K., Siddiqa, A., Pentland, I., Feeney, K. M., Knapman, A., Davies, R., Androphy, E. J. & Parish, J. L. Mar 2017 In : Journal of Virology. 91, 5, 18 p., e02305-16

    Research output: Research - peer-reviewArticle

  2. ARID3B: a novel regulator of the Kaposi’s sarcoma-associated herpesvirus lytic cycle

    Wood, J., Boyne, J., Paulus, C., Jackson, B., Nevels, M. M., Whitehouse, A. & Hughes, D. J. Oct 2016 In : Journal of Virology. 90, 20, p. 9543-9555

    Research output: Research - peer-reviewArticle

  3. Assessing host-virus codivergence for close relatives of Merkel cell polyomavirus infecting African great apes

    Madinda, N. F. , Ehlers, B. , Wertheim, J. O. , Akoua-Koffi, C. , Bergl, R. A. , Boesch, C. , Akonkwa, D. B. M. , Eckardt, W. , Fruth, B. , Gillespie, T. R. , Gray, M. , Hohmann, G. , Karhemere, S. , Kujirakwinja, D. , Langergraber, K. , Muyembe, J. J. , Nishuli, R. , Pauly, M. , Petrzelkova, K. J. , Robbins, M. M. & 8 others Todd, A., Schubert, G., Stoinski, T. S., Wittig, R. M., Zuberbühler, K., Peeters, M., Leendertz, F. H. & Calvignac-Spencer, S. Oct 2016 In : Journal of Virology. 90, 19, p. 8531-8541 11 p.

    Research output: Research - peer-reviewArticle

  4. Human IFIT1 inhibits mRNA translation of rubulaviruses but not other members of the Paramyxoviridae family

    Young, D. F., Andrejeva, J., Li, X., Inesta-Vaquera, F., Dong, C., Cowling, V. H., Goodbourn, S. & Randall, R. E. Oct 2016 In : Journal of Virology. 90, 20, p. 9446-9456

    Research output: Research - peer-reviewArticle

Related by journal

  1. Journal of Virology (Journal)

    Richard Michael Elliott (Editor)
    20052013

    Activity: Publication peer-review and editorial workEditor of research journal

ID: 243686503