Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites

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

doi:10.1021/acs.jmedchem.6c00823

Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites

Barbara Forte
, Fiona Bellany
, Peter S. Campbell
, Giulia Chemi
, Alice Dawson
, Mark Anderson
, Yaw Aniweh
, Anna Y. Burkhard
, Anna Caroline Campos Aguiar
, Alisje Churchyard
, Caitlin A. Cooper
, Amalia dos Santos Ferreira
, Mufuliat Toyin Famodimu
, Francis G. Fang
, Xiao Hu
, Tonnie Huijs
, Delphine Baud
, Chimed Jansen
, María Belén Jiménez-Díaz
, Roger Bonnert

Susan Boyd, Benigno Crespo-Fernandez, Branko Mitasev, Simone Montagna, Sachel Mok, Dinakaran Murugesan, Sunil K. Narwal, Neil R. Norcross, John Okombo, Heekuk Park, Caroline Peet, Dhelio B. Pereira, John M. Post, Janette Reader, Jennifer Riley, David A. Robinson, Raku Shinkyo, Frederick R. C. Simeons, Laura Simpson, Alasdair Smith, Dennis Smith, Josefine Striepen, Carolina B. G. Teles, Rianne van der Laak, Anne Catrin Uhlemann, Amélie Vantaux, Caroline Wilson, Benoît Witkowski, Gavin Wood, Tomas Yeo, Fabio Zuccotto, Iñigo Angulo-Barturen, Jake Baum, Judith M. Bolscher, Rafael V. Guido, Lyn-Marie Birkholtz, Michael J. Delves, Laurent Dembélé, David A. Fidock, Francisco-Javier Gamo, Dennis E. Kyle, Steven P. Maher, Jean Popovici, Chris Walpole, Fabian Gusovsky, Paul A. Willis, Kevin D. Read (Lead / Corresponding author), Ian H. Gilbert (Lead / Corresponding author), Beatriz Baragana (Lead / Corresponding author)

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	13820-13855
Number of pages	36
Journal	Journal of Medicinal Chemistry
Volume	69
Issue number	11
Early online date	2 Jun 2026
DOIs	https://doi.org/10.1021/acs.jmedchem.6c00823
Publication status	Published - 11 Jun 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.6c00823Licence: CC BY

Final Published VersionFinal published version, 7.87 MBLicence: CC BY

State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B. (Investigator), Lilley, D. (Investigator), Owen-Hughes, T. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/03/12 → 28/02/17
Project: Research

Cite this

Forte, B., Bellany, F., Campbell, P. S., Chemi, G., Dawson, A., Anderson, M., Aniweh, Y., Burkhard, A. Y., Aguiar, A. C. C., Churchyard, A., Cooper, C. A., Ferreira, A. D. S., Famodimu, M. T., Fang, F. G., Hu, X., Huijs, T., Baud, D., Jansen, C., Jiménez-Díaz, M. B., ... Baragana, B. (2026). Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites. Journal of Medicinal Chemistry, 69(11), 13820-13855. https://doi.org/10.1021/acs.jmedchem.6c00823

@article{5bff337adf2d425da349531e8354f76e,

title = "Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites",

abstract = "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.",

author = "Barbara Forte and Fiona Bellany and Campbell, \{Peter S.\} and Giulia Chemi and Alice Dawson and Mark Anderson and Yaw Aniweh and Burkhard, \{Anna Y.\} and Aguiar, \{Anna Caroline Campos\} and Alisje Churchyard and Cooper, \{Caitlin A.\} and Ferreira, \{Amalia dos Santos\} and Famodimu, \{Mufuliat Toyin\} and Fang, \{Francis G.\} and Xiao Hu and Tonnie Huijs and Delphine Baud and Chimed Jansen and Jim{\'e}nez-D{\'i}az, \{Mar{\'i}a Bel{\'e}n\} and Roger Bonnert and Susan Boyd and Benigno Crespo-Fernandez and Branko Mitasev and Simone Montagna and Sachel Mok and Dinakaran Murugesan and Narwal, \{Sunil K.\} and Norcross, \{Neil R.\} and John Okombo and Heekuk Park and Caroline Peet and Pereira, \{Dhelio B.\} and Post, \{John M.\} and Janette Reader and Jennifer Riley and Robinson, \{David A.\} and Raku Shinkyo and Simeons, \{Frederick R. C.\} and Laura Simpson and Alasdair Smith and Dennis Smith and Josefine Striepen and Teles, \{Carolina B. G.\} and \{van der Laak\}, Rianne and Uhlemann, \{Anne Catrin\} and Am{\'e}lie Vantaux and Caroline Wilson and Beno{\^i}t Witkowski and Gavin Wood and Tomas Yeo and Fabio Zuccotto and I{\~n}igo Angulo-Barturen and Jake Baum and Bolscher, \{Judith M.\} and Guido, \{Rafael V.\} and Lyn-Marie Birkholtz and Delves, \{Michael J.\} and Laurent Demb{\'e}l{\'e} and Fidock, \{David A.\} and Francisco-Javier Gamo and Kyle, \{Dennis E.\} and Maher, \{Steven P.\} and Jean Popovici and Chris Walpole and Fabian Gusovsky and Willis, \{Paul A.\} and Read, \{Kevin D.\} and Gilbert, \{Ian H.\} and Beatriz Baragana",

note = "Publisher Copyright: {\textcopyright} 2026 The Authors. Published by American Chemical Society.",

year = "2026",

month = jun,

day = "11",

doi = "10.1021/acs.jmedchem.6c00823",

language = "English",

volume = "69",

pages = "13820--13855",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "11",

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Forte, B , Bellany, F , Campbell, PS, Chemi, G, Dawson, A, Anderson, M, Aniweh, Y, Burkhard, AY, Aguiar, ACC, Churchyard, A, Cooper, CA, Ferreira, ADS, Famodimu, MT, Fang, FG, Hu, X, Huijs, T, Baud, D, Jansen, C, Jiménez-Díaz, MB, Bonnert, R, Boyd, S, Crespo-Fernandez, B, Mitasev, B, Montagna, S, Mok, S, Murugesan, D, Narwal, SK, Norcross, NR, Okombo, J, Park, H, Peet, C, Pereira, DB, Post, JM, Reader, J, Riley, J, Robinson, DA, Shinkyo, R, Simeons, FRC , Simpson, L, Smith, A, Smith, D, Striepen, J, Teles, CBG, van der Laak, R, Uhlemann, AC, Vantaux, A, Wilson, C, Witkowski, B, Wood, G, Yeo, T, Zuccotto, F, Angulo-Barturen, I, Baum, J, Bolscher, JM, Guido, RV, Birkholtz, L-M, Delves, MJ, Dembélé, L, Fidock, DA, Gamo, F-J, Kyle, DE, Maher, SP, Popovici, J, Walpole, C, Gusovsky, F, Willis, PA, Read, KD , Gilbert, IH & Baragana, B 2026, 'Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites', Journal of Medicinal Chemistry, vol. 69, no. 11, pp. 13820-13855. https://doi.org/10.1021/acs.jmedchem.6c00823

TY - JOUR

T1 - Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites

AU - Forte, Barbara

AU - Bellany, Fiona

AU - Campbell, Peter S.

AU - Chemi, Giulia

AU - Dawson, Alice

AU - Anderson, Mark

AU - Aniweh, Yaw

AU - Burkhard, Anna Y.

AU - Aguiar, Anna Caroline Campos

AU - Churchyard, Alisje

AU - Cooper, Caitlin A.

AU - Ferreira, Amalia dos Santos

AU - Famodimu, Mufuliat Toyin

AU - Fang, Francis G.

AU - Hu, Xiao

AU - Huijs, Tonnie

AU - Baud, Delphine

AU - Jansen, Chimed

AU - Jiménez-Díaz, María Belén

AU - Bonnert, Roger

AU - Boyd, Susan

AU - Crespo-Fernandez, Benigno

AU - Mitasev, Branko

AU - Montagna, Simone

AU - Mok, Sachel

AU - Murugesan, Dinakaran

AU - Narwal, Sunil K.

AU - Norcross, Neil R.

AU - Okombo, John

AU - Park, Heekuk

AU - Peet, Caroline

AU - Pereira, Dhelio B.

AU - Post, John M.

AU - Reader, Janette

AU - Riley, Jennifer

AU - Robinson, David A.

AU - Shinkyo, Raku

AU - Simeons, Frederick R. C.

AU - Simpson, Laura

AU - Smith, Alasdair

AU - Smith, Dennis

AU - Striepen, Josefine

AU - Teles, Carolina B. G.

AU - van der Laak, Rianne

AU - Uhlemann, Anne Catrin

AU - Vantaux, Amélie

AU - Wilson, Caroline

AU - Witkowski, Benoît

AU - Wood, Gavin

AU - Yeo, Tomas

AU - Zuccotto, Fabio

AU - Angulo-Barturen, Iñigo

AU - Baum, Jake

AU - Bolscher, Judith M.

AU - Guido, Rafael V.

AU - Birkholtz, Lyn-Marie

AU - Delves, Michael J.

AU - Dembélé, Laurent

AU - Fidock, David A.

AU - Gamo, Francisco-Javier

AU - Kyle, Dennis E.

AU - Maher, Steven P.

AU - Popovici, Jean

AU - Walpole, Chris

AU - Gusovsky, Fabian

AU - Willis, Paul A.

AU - Read, Kevin D.

AU - Gilbert, Ian H.

AU - Baragana, Beatriz

PY - 2026/6/11

Y1 - 2026/6/11

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.6c00823

DO - 10.1021/acs.jmedchem.6c00823

M3 - Article

C2 - 42227818

SN - 0022-2623

VL - 69

SP - 13820

EP - 13855

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites

Abstract

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State-of-the-Art Facilities for Structural Biology at the University of Dundee

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