Browsing by Author "Soares da Costa, TP"

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    Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity.
    (Springer Nature, 2023-05-22) Mackie, ERR; Barrow, AS; Giel, MC; Hulett, MD; Gendall, AR; Panjikar, S; Soares da Costa, TP
    Herbicide resistance represents one of the biggest threats to our natural environment and agricultural sector. Thus, new herbicides are urgently needed to tackle the rise in herbicide-resistant weeds. Here, we employed a novel strategy to repurpose a 'failed' antibiotic into a new and target-specific herbicidal compound. Specifically, we identified an inhibitor of bacterial dihydrodipicolinate reductase (DHDPR), an enzyme involved in lysine biosynthesis in plants and bacteria, that exhibited no antibacterial activity but severely attenuated germination of the plant Arabidopsis thaliana. We confirmed that the inhibitor targets plant DHDPR orthologues in vitro, and exhibits no toxic effects against human cell lines. A series of analogues were then synthesised with improved efficacy in germination assays and against soil-grown A. thaliana. We also showed that our lead compound is the first lysine biosynthesis inhibitor with activity against both monocotyledonous and dicotyledonous weed species, by demonstrating its effectiveness at reducing the germination and growth of Lolium rigidum (rigid ryegrass) and Raphanus raphanistrum (wild radish). These results provide proof-of-concept that DHDPR inhibition may represent a much-needed new herbicide mode of action. Furthermore, this study exemplifies the untapped potential of repurposing 'failed' antibiotic scaffolds to fast-track the development of herbicide candidates targeting the respective plant enzymes. © The Authors - Open Access Creative Commons Attribution 4.0 International Licence.
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    Understanding viral host interactions that modulate nuclear transport and innate immunity
    (International Union of Crystallography, 2021-08-14) Tsimbalyuk, S; Smith, KM; Edwards, MR; Cross, EM; Batra, J; Soares da Costa, TP; Aragão, A; Basler, CF; Forwood, JK
    RNA viruses such as coronaviruses, flaviviruses, and henipaviruses represent major international health threats. Whilst these viruses replicate in the cytoplasm, they encode accessory proteins that target the host nuclear transport machinery to suppress innate immune pathways. Specifically, these virus proteins target the nuclear import receptor importin-a (IMPa) and inhibit host immune responses from entering the nucleus and triggering interferon (IFN) release. This immune evasion strategy is a critical component of virus pathogenicity, yet details of these interactions (including mechanism(s) of binding specificity with IMPa isoforms) remain unresolved. Here we describe the interfaces between these viral immune regulatory proteins and specific IMPA host receptors as targets for development of novel antivirals. © The Authors