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dc.contributor.authorDickie, Emily A
dc.contributor.authorRonin, Céline
dc.contributor.authorSá, Mónica
dc.contributor.authorCiesielski, Fabrice
dc.contributor.authorTrouche, Nathalie
dc.contributor.authorTavares, Joana
dc.contributor.authorSantarem, Nuno
dc.contributor.authorMajor, Louise L
dc.contributor.authorPemberton, Iain K
dc.contributor.authorMacDougall, Jane
dc.contributor.authorSmith, Terry K
dc.contributor.authorCordeiro-da-Silva, Anabela
dc.contributor.authorCiapetti, Paola
dc.date.accessioned2021-10-18T23:39:08Z
dc.date.available2021-10-18T23:39:08Z
dc.date.issued2021-04-19
dc.identifier.citationDickie , 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.01892-20en
dc.identifier.issn0066-4804
dc.identifier.otherPURE: 274062877
dc.identifier.otherPURE UUID: 0d85a37c-90b8-4238-8024-7861ae06e30f
dc.identifier.otherJisc: c1219320df78495994877bd79c596f7a
dc.identifier.otherPubMed: 33875438
dc.identifier.otherpii: AAC.01892-20
dc.identifier.otherORCID: /0000-0001-5287-4488/work/93514353
dc.identifier.otherScopus: 85108282526
dc.identifier.otherWOS: 000707841700037
dc.identifier.urihttp://hdl.handle.net/10023/24164
dc.descriptionFunding 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).en
dc.description.abstractNeglected 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.
dc.language.isoeng
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen
dc.rightsCopyright © 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.en
dc.subjectNeglected tropical diseasesen
dc.subjectLeishmania infantumen
dc.subjectLeishmaniasisen
dc.subjectRibose 5-phosphate isomeraseen
dc.subjectInhibitoren
dc.subjectScreeningen
dc.subjectThermal shiften
dc.subjectAnti-parasiticen
dc.subjectProtein crystal structureen
dc.subjectQD Chemistryen
dc.subjectQR Microbiologyen
dc.subjectRM Therapeutics. Pharmacologyen
dc.subjectNDASen
dc.subject.lccQDen
dc.subject.lccQRen
dc.subject.lccRMen
dc.titleTowards chemical validation of Leishmania infantum ribose 5-phosphate isomerase as a drug targeten
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews.Arctic Research Centreen
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1128/AAC.01892-20
dc.description.statusPeer revieweden
dc.date.embargoedUntil2021-10-19


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