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DOI 10.1021/acs.jmedchem.6c00823

Медицинская библиотека · Journal of medicinal chemistry · 2026

Structure-Guided Optimization of Novel Inhibitors of Plasmodium Lysyl-tRNA Synthetase with Multistage Activity against Malaria Parasites.

Forte Barbara, Bellany Fiona, Campbell Peter S, Chemi Giulia, Dawson Alice, Anderson Mark, Aniweh Yaw, Burkhard Anna Y, Aguiar Anna Caroline Campos, Churchyard Alisje, Cooper Caitlin A, Dos Santos Ferreira Amália, Famodimu Mufuliat Toyin, Fang Francis G, Hu Xiao, Huijs Tonnie, Baud Delphine, Jansen Chimed, Jiménez Díaz María Belén, Bonnert Roger, Boyd Susan, Crespo-Fernández Benigno, Mitasev Branko, Montagna Simone, Mok Sachel, Murugesan Dinakaran, Narwal Sunil K, Norcross Neil R, Okombo John, Park Heekuk, Peet Caroline, Pereira Dhelio B, Post John M, Reader Janette, Riley Jennifer, Robinson David A, Shinkyo Raku, Simeons Frederick R C, Simpson Laura, Smith Alasdair, Smith Dennis, Striepen Josefine, Teles Carolina B G, van der Laak Rianne, Uhlemann Anne-Catrin, Vantaux Amélie, Wilson Caroline, Witkowski Benoît, Wood Gavin, Yeo Tomas, Zuccotto Fabio, Angulo-Barturen Iñigo, Baum Jake, Bolscher Judith M, Guido Rafael Victorio Carvalho, Birkholtz Lyn-Marié, Delves Michael J, Dembele Laurent, Fidock David A, Gamo Francisco Javier, Kyle Dennis E, Maher Steven P, Popovici Jean, Walpole Chris, Gusovsky Fabian, Willis Paul A, Read Kevin D, Gilbert Ian H, Baragaña Beatriz

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Аннотация

A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγnull (SCID) mouse model. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor (30) with an extended half-life to reduce the dose regimen to a single-dose cure. Compound 30 displayed a long half-life across preclinical species, favorable safety, and activity across Plasmodium species as well as against drug-resistant and sensitive P. falciparum strains and field isolates. Unfortunately, 30 lacked oral bioavailability, which could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future KRS programs in delivering a clinical candidate with this novel mode of action.

Для цитирования: Forte Barbara, Bellany Fiona, Campbell Peter S, Chemi Giulia, Dawson Alice, Anderson Mark, Aniweh Yaw, Burkhard Anna Y, Aguiar Anna Caroline Campos, Churchyard Alisje, Cooper Caitlin A, Dos Santos Ferreira Amália, Famodimu Mufuliat Toyin, Fang Francis G, Hu Xiao, Huijs Tonnie, Baud Delphine, Jansen Chimed, Jiménez Díaz María Belén, Bonnert Roger, Boyd Susan, Crespo-Fernández Benigno, Mitasev Branko, Montagna Simone, Mok Sachel, Murugesan Dinakaran, Narwal Sunil K, Norcross Neil R, Okombo John, Park Heekuk, Peet Caroline, Pereira Dhelio B, Post John M, Reader Janette, Riley Jennifer, Robinson David A, Shinkyo Raku, Simeons Frederick R C, Simpson Laura, Smith Alasdair, Smith Dennis, Striepen Josefine, Teles Carolina B G, van der Laak Rianne, Uhlemann Anne-Catrin, Vantaux Amélie, Wilson Caroline, Witkowski Benoît, Wood Gavin, Yeo Tomas, Zuccotto Fabio, Angulo-Barturen Iñigo, Baum Jake, Bolscher Judith M, Guido Rafael Victorio Carvalho, Birkholtz Lyn-Marié, Delves Michael J, Dembele Laurent, Fidock David A, Gamo Francisco Javier, Kyle Dennis E, Maher Steven P, Popovici Jean, Walpole Chris, Gusovsky Fabian, Willis Paul A, Read Kevin D, Gilbert Ian H, Baragaña Beatriz. Structure-Guided Optimization of Novel Inhibitors of Plasmodium Lysyl-tRNA Synthetase with Multistage Activity against Malaria Parasites.. Journal of medicinal chemistry. 2026. DOI: 10.1021/acs.jmedchem.6c00823.

Предметные рубрики MeSH

AnimalsAntimalarialsLysine-tRNA LigaseStructure-Activity RelationshipPlasmodium falciparumHumansMiceMalariaEnzyme InhibitorsMice, SCIDPyrimidinesPlasmodium
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