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DOI 10.1038/nature14451

Медицинская библиотека · Nature · 2015

A novel multiple-stage antimalarial agent that inhibits protein synthesis.

Baragaña Beatriz, Hallyburton Irene, Lee Marcus C S, Norcross Neil R, Grimaldi Raffaella, Otto Thomas D, Proto William R, Blagborough Andrew M, Meister Stephan, Wirjanata Grennady, Ruecker Andrea, Upton Leanna M, Abraham Tara S, Almeida Mariana J, Pradhan Anupam, Porzelle Achim, Luksch Torsten, Martínez María Santos, Luksch Torsten, Bolscher Judith M, Woodland Andrew, Norval Suzanne, Zuccotto Fabio, Thomas John, Simeons Frederick, Stojanovski Laste, Osuna-Cabello Maria, Brock Paddy M, Churcher Tom S, Sala Katarzyna A, Zakutansky Sara E, Jiménez-Díaz María Belén, Sanz Laura Maria, Riley Jennifer, Basak Rajshekhar, Campbell Michael, Avery Vicky M, Sauerwein Robert W, Dechering Koen J, Noviyanti Rintis, Campo Brice, Frearson Julie A, Angulo-Barturen Iñigo, Ferrer-Bazaga Santiago, Gamo Francisco Javier, Wyatt Paul G, Leroy Didier, Siegl Peter, Delves Michael J, Kyle Dennis E, Wittlin Sergio, Marfurt Jutta, Price Ric N, Sinden Robert E, Winzeler Elizabeth A, Charman Susan A, Bebrevska Lidiya, Gray David W, Campbell Simon, Fairlamb Alan H, Willis Paul A, Rayner Julian C, Fidock David A, Read Kevin D, Gilbert Ian H

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Для цитирования: Baragaña Beatriz, Hallyburton Irene, Lee Marcus C S, Norcross Neil R, Grimaldi Raffaella, Otto Thomas D, Proto William R, Blagborough Andrew M, Meister Stephan, Wirjanata Grennady, Ruecker Andrea, Upton Leanna M, Abraham Tara S, Almeida Mariana J, Pradhan Anupam, Porzelle Achim, Luksch Torsten, Martínez María Santos, Luksch Torsten, Bolscher Judith M, Woodland Andrew, Norval Suzanne, Zuccotto Fabio, Thomas John, Simeons Frederick, Stojanovski Laste, Osuna-Cabello Maria, Brock Paddy M, Churcher Tom S, Sala Katarzyna A, Zakutansky Sara E, Jiménez-Díaz María Belén, Sanz Laura Maria, Riley Jennifer, Basak Rajshekhar, Campbell Michael, Avery Vicky M, Sauerwein Robert W, Dechering Koen J, Noviyanti Rintis, Campo Brice, Frearson Julie A, Angulo-Barturen Iñigo, Ferrer-Bazaga Santiago, Gamo Francisco Javier, Wyatt Paul G, Leroy Didier, Siegl Peter, Delves Michael J, Kyle Dennis E, Wittlin Sergio, Marfurt Jutta, Price Ric N, Sinden Robert E, Winzeler Elizabeth A, Charman Susan A, Bebrevska Lidiya, Gray David W, Campbell Simon, Fairlamb Alan H, Willis Paul A, Rayner Julian C, Fidock David A, Read Kevin D, Gilbert Ian H. A novel multiple-stage antimalarial agent that inhibits protein synthesis.. Nature. 2015. DOI: 10.1038/nature14451.

Предметные рубрики MeSH

AnimalsAntimalarialsDrug DiscoveryFemaleGene Expression RegulationLife Cycle StagesLiverMalariaMaleModels, MolecularPeptide Elongation Factor 2PlasmodiumPlasmodium bergheiPlasmodium falciparumPlasmodium vivaxProtein BiosynthesisQuinolines
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