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. Polycyclic ethers and an unexpected dearomatisation reaction during studies towards the bioactive alkaloid, perophoramidine

    Johnston, C. A., Wilkie, R. P., Krauss, H., Neal, A. R., Slawin, A. M. Z., Lebl, T. & Westwood, N. J. 28 Apr 2018 In : Tetrahedron. In press

    Research output: Research - peer-reviewArticle

  3. Design, synthesis and biological evaluation of piperazinyl-β-carbolinederivatives as anti-leishmanial agents

    Ashok, P., Chander, S., Smith, T. K. & Sankaranarayanan, M. 25 Apr 2018 In : European Journal Of Medicinal Chemistry. 150, p. 559-566 8 p.

    Research output: Research - peer-reviewArticle

  4. Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib

    Ladds, M. J. G. W., Pastor-Fernández, A., Popova, G., van Leeuwen, I. M. M., Eng, K. E., Drummond, C. J., Johansson, L., Svensson, R., Westwood, N. J., McCarthy, A. R., Tholander, F., Popa, M., Lane, D. P., McCormack, E., McInerney, G. M., Bhatia, R. & Laín, S. 23 Apr 2018 In : PLoS One. 13, 4, 21 p., e0195956

    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