Biochemistry and Pharmacology - Research Publications

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Author: Griffin, Michael × End date: 2021 × Start date: 2021 ×

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    Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome
    Xie, SC ; Metcalfe, RD ; Mizutani, H ; Puhalovich, T ; Hanssen, E ; Morton, CJ ; Du, Y ; Dogovski, C ; Huang, S-C ; Ciavarri, J ; Hales, P ; Griffin, RJ ; Cohen, LH ; Chuang, B-C ; Wittlin, S ; Deni, I ; Yeo, T ; Ward, KE ; Barry, DC ; Liu, B ; Gillett, DL ; Crespo-Fernandez, BF ; Ottilie, S ; Mittal, N ; Churchyard, A ; Ferguson, D ; Aguiar, ACC ; Guido, RVC ; Baum, J ; Hanson, KK ; Winzeler, EA ; Gamo, F-J ; Fidock, DA ; Baud, D ; Parker, MW ; Brand, S ; Dick, LR ; Griffin, MDW ; Gould, AE ; Tilley, L (NATL ACAD SCIENCES, 2021-09-28)
    The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.
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    Mechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism
    Horne, CR ; Venugopal, H ; Panjikar, S ; Wood, DM ; Henrickson, A ; Brookes, E ; North, RA ; Murphy, JM ; Friemann, R ; Griffin, MDW ; Ramm, G ; Demeler, B ; Dobson, RCJ (NATURE PORTFOLIO, 2021-03-31)
    Bacteria respond to environmental changes by inducing transcription of some genes and repressing others. Sialic acids, which coat human cell surfaces, are a nutrient source for pathogenic and commensal bacteria. The Escherichia coli GntR-type transcriptional repressor, NanR, regulates sialic acid metabolism, but the mechanism is unclear. Here, we demonstrate that three NanR dimers bind a (GGTATA)3-repeat operator cooperatively and with high affinity. Single-particle cryo-electron microscopy structures reveal the DNA-binding domain is reorganized to engage DNA, while three dimers assemble in close proximity across the (GGTATA)3-repeat operator. Such an interaction allows cooperative protein-protein interactions between NanR dimers via their N-terminal extensions. The effector, N-acetylneuraminate, binds NanR and attenuates the NanR-DNA interaction. The crystal structure of NanR in complex with N-acetylneuraminate reveals a domain rearrangement upon N-acetylneuraminate binding to lock NanR in a conformation that weakens DNA binding. Our data provide a molecular basis for the regulation of bacterial sialic acid metabolism.