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  • Journal article
    Kahan R, Worm D, Vieira de Castro G, Ng C, Barnard Aet al., 2021,

    Modulators of protein–protein interactions as antimicrobial agents

    , RSC Chemical Biology, Vol: 2, Pages: 387-409, ISSN: 2633-0679

    Protein–Protein interactions (PPIs) are involved in a myriad of cellular processes in all living organisms and the modulation of PPIs is already under investigation for the development of new drugs targeting cancers, autoimmune diseases and viruses. PPIs are also involved in the regulation of vital functions in bacteria and, therefore, targeting bacterial PPIs offers an attractive strategy for the development of antibiotics with novel modes of action. The latter are urgently needed to tackle multidrug-resistant and multidrug-tolerant bacteria. In this review, we describe recent developments in the modulation of PPIs in pathogenic bacteria for antibiotic development, including advanced small molecule and peptide inhibitors acting on bacterial PPIs involved in division, replication and transcription, outer membrane protein biogenesis, with an additional focus on toxin–antitoxin systems as upcoming drug targets.

  • Journal article
    Rueda-Zubiaurre A, Yahiya S, Fischer O, Hu X, Saunders C, Sharma S, Straschil U, Shen J, Tate EW, Delves M, Baum J, Barnard A, Fuchter MJet al., 2020,

    Structure-activity relationship studies of a novel class of transmission blocking antimalarials targeting male gametes.

    , Journal of Medicinal Chemistry, Vol: 63, Pages: 2240-2262, ISSN: 0022-2623

    Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention towards that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.

  • Journal article
    Flack T, Romain C, White A, Haycock P, Barnard Aet al., 2019,

    Design, synthesis and conformational analysis of oligobenzanilides as multi-facial alpha-helix mimetics

    , Organic Letters, Vol: 21, Pages: 4433-4438, ISSN: 1523-7052

    The design, synthesis, and conformationalanalysis of an oligobenzanilide helix mimetic scaffold capableof simultaneous mimicry of two faces of an α-helix is reported.The synthetic methodology provides access to diversemonomer building blocks amenable to solid-phase assemblyin just four synthetic steps. The conformational flexibility ofmodel dimers was investigated using a combination of solidand solution state methodologies supplemented with DFTcalculations. The lack of noncovalent constraints allows forsignificant conformational plasticity in the scaffold, thuspermitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.

  • Journal article
    Delves M, Miguel-Blanco C, Matthews H, Molina I, Ruecker A, Yahiya S, Straschil U, Abraham M, Leon-Diaz ML, Fischer O, Zubiaurre A, Brandt J, Cortes A, Barnard A, Fuchter M, Calderon F, Winzeler E, Sinden R, Herreros E, Gamo FJ, Baum Jet al., 2018,

    A high throughput screen for next-generation leads targeting malaria parasite transmission

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.

  • Journal article
    Arrata I, Barnard A, Tomlinson DC, Wilson AJet al., 2017,

    Interfacing native and non-native peptides: using Affimers to recognise α-helix mimicking foldamers

    , Chemical Communications, Vol: 53, Pages: 2834-2837, ISSN: 1359-7345

    Selection methods are used to identify Affimers that recognise α-helix mimicking N-alkylated aromatic oligoamides thus demonstrating foldamer and natural α-amino acid codes are compatible.

  • Journal article
    Azzarito V, Rowell P, Barnard A, Edwards TA, Macdonald A, Warriner SL, Wilson AJet al., 2016,

    Probing Protein Surfaces: QSAR Analysis with Helix Mimetics

    , Chembiochem, Vol: 17, Pages: 768-773, ISSN: 1439-7633

    α-Helix-mediated protein–protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.

  • Journal article
    Barnard A, Long K, Martin HL, Miles JA, Edwards TA, Tomlinson DC, Macdonald A, Wilson AJet al., 2015,

    Selective and potent proteomimetic inhibitors of intracellular protein–protein interactions

    , Angewandte Chemie - International Edition, Vol: 54, Pages: 2960-2965, ISSN: 1433-7851

    Inhibition of protein–protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed “proteomimetics”, which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N-alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.

  • Journal article
    Barnard A, Miles JA, Burslem GM, Barker AM, Wilson AJet al., 2014,

    Multivalent helix mimetics for PPI-inhibition

    , Organic & Biomolecular Chemistry, Vol: 13, Pages: 258-264, ISSN: 1477-0539

    The exploitation of multivalent ligands for the inhibition of protein–protein interactions has not yet been explored as a supramolecular design strategy. This is despite the fact that protein–protein interactions typically occur within the context of multi-protein complexes and frequently exploit avidity effects or co-operative binding interactions to achieve high affinity interactions. In this paper we describe preliminary studies on the use of a multivalent N-alkylated aromatic oligoamide helix mimetic for inhibition of p53/hDM2 and establish that protein dimerisation is promoted, rather than enhanced binding resulting from a higher effective concentration of the ligand.

  • Journal article
    Barnard A, Posocco P, Fermeglia M, Tschiche A, Calderon M, Pricl S, Smith DKet al., 2014,

    Double-degradable responsive self-assembled multivalent arrays - temporary nanoscale recognition between dendrons and DNA

    , ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 12, Pages: 446-455, ISSN: 1477-0520
  • Journal article
    Barnard A, Long K, Yeo DJ, Miles JA, Azzarito V, Burslem GM, Prabhakaran P, Edwards TA, Wilson AJet al., 2014,

    Orthogonal functionalisation of alpha-helix mimetics

    , ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 12, Pages: 6794-6799, ISSN: 1477-0520

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