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Towards chemical validation of Leishmania infantum ribose 5-phosphate isomerase as a drug target

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Date
19/04/2021
Author
Dickie, Emily A
Ronin, Céline
Sá, Mónica
Ciesielski, Fabrice
Trouche, Nathalie
Tavares, Joana
Santarem, Nuno
Major, Louise L
Pemberton, Iain K
MacDougall, Jane
Smith, Terry K
Cordeiro-da-Silva, Anabela
Ciapetti, Paola
Keywords
Neglected tropical diseases
Leishmania infantum
Leishmaniasis
Ribose 5-phosphate isomerase
Inhibitor
Screening
Thermal shift
Anti-parasitic
Protein crystal structure
QD Chemistry
QR Microbiology
RM Therapeutics. Pharmacology
NDAS
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Abstract
Neglected tropical diseases caused by kinetoplastid parasites (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) place a significant health and economic burden on developing nations worldwide. Current therapies are largely out-dated, inadequate and facing mounting drug resistance from the causative parasites. Thus, there is an urgent need for drug discovery and development. Target-led drug discovery approaches have focused on the identification of parasite enzymes catalysing essential biochemical processes, which significantly differ from equivalent proteins found in humans, thereby providing potentially exploitable therapeutic windows. One such target is ribose 5-phosphate isomerase B (RpiB), an enzyme involved in the non-oxidative branch of the pentose phosphate pathway, which catalyses the inter-conversion of D-ribose 5-phosphate and D-ribulose 5-phosphate. Although protozoan RpiB has been the focus of numerous targeted studies, compounds capable of selectively inhibiting this parasite enzyme have not been identified. Here, we present the results of a fragment library screening against Leishmania infantum RpiB, performed using thermal shift analysis. Hit fragments were shown to be effective inhibitors of LiRpiB in activity assays, and several were capable of selectively inhibiting parasite growth in vitro. These results support the identification of LiRpiB as a validated therapeutic target. The X-ray crystal structure of apo LiRpiB was also solved, permitting docking studies to assess how hit fragments might interact with LiRpiB to inhibit its activity. Overall, this work will guide structure-based development of LiRpiB inhibitors as anti-leishmanial agents.
Citation
Dickie , E A , Ronin , C , Sá , M , Ciesielski , F , Trouche , N , Tavares , J , Santarem , N , Major , L L , Pemberton , I K , MacDougall , J , Smith , T K , Cordeiro-da-Silva , A & Ciapetti , P 2021 , ' Towards chemical validation of Leishmania infantum ribose 5-phosphate isomerase as a drug target ' , Antimicrobial Agents and Chemotherapy , vol. Early . https://doi.org/10.1128/AAC.01892-20
Publication
Antimicrobial Agents and Chemotherapy
Status
Peer reviewed
DOI
https://doi.org/10.1128/AAC.01892-20
ISSN
0066-4804
Type
Journal article
Rights
Copyright © 2021 American Society for Microbiology. All Rights Reserved. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1128/AAC.01892-20.
Description
Funding from the European Community's Seventh Framework Programme under grant agreements No. 602773 (Project KINDRED) was received for all partners in this work. This work also received funds from FCT - Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior through the Research Unit No. 4293 and project POCI-01-0145-FEDER-031013 (PTDC/SAUPAR/31013/2017 to NS); Individual funding from FCT through SFRH/BD/133485/2017 (to MS) and CEECIND/02362/2017 (to JT).
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/24164

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