Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Laura E. de Vries; Patrick A.M. Jansen; Catalina Barcelo; Justin Munro; Julie M.J. Verhoef; Charisse Flerida A. Pasaje; Kelly Rubiano; Josefine Striepen; Nada Abla; Luuk Berning; Judith M. Bolscher; Claudia Demarta-Gatsi; Rob W.M. Henderson; Tonnie Huijs; Karin M.J. Koolen; Patrick K. Tumwebaze; Tomas Yeo; Anna C.C. Aguiar; Iñigo Angulo-Barturen; Alisje Churchyard; Jake Baum; Benigno Crespo Fernández; Aline Fuchs; Francisco Javier Gamo; Rafael V.C. Guido; María Belén Jiménez-Diaz; Dhelio B. Pereira; Rosemary Rochford; Camille Roesch; Laura M. Sanz; Graham Trevitt; Benoit Witkowski; Sergio Wittlin; Roland A. Cooper; Philip J. Rosenthal; Robert W. Sauerwein; Joost Schalkwijk; Pedro H.H. Hermkens; Roger V. Bonnert; Brice Campo; David A. Fidock; Manuel Llinás; Jacquin C. Niles; Taco W.A. Kooij; Koen J. Dechering

doi:10.1038/s41467-022-29688-5

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Laura E. de Vries, Patrick A.M. Jansen, Catalina Barcelo, Justin Munro, Julie M.J. Verhoef, Charisse Flerida A. Pasaje, Kelly Rubiano, Josefine Striepen, Nada Abla, Luuk Berning, Judith M. Bolscher, Claudia Demarta-Gatsi, Rob W.M. Henderson, Tonnie Huijs, Karin M.J. Koolen, Patrick K. Tumwebaze, Tomas Yeo, Anna C.C. Aguiar, Iñigo Angulo-Barturen, Alisje ChurchyardJake Baum, Benigno Crespo Fernández, Aline Fuchs, Francisco Javier Gamo, Rafael V.C. Guido, María Belén Jiménez-Diaz, Dhelio B. Pereira, Rosemary Rochford, Camille Roesch, Laura M. Sanz, Graham Trevitt, Benoit Witkowski, Sergio Wittlin, Roland A. Cooper, Philip J. Rosenthal, Robert W. Sauerwein, Joost Schalkwijk, Pedro H.H. Hermkens, Roger V. Bonnert, Brice Campo, David A. Fidock, Manuel Llinás, Jacquin C. Niles, Taco W.A. Kooij, Koen J. Dechering

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Abstract

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.

Original language	English (US)
Article number	2158
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-29688-5
State	Published - Dec 2022

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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de Vries, L. E., Jansen, P. A. M., Barcelo, C., Munro, J., Verhoef, J. M. J., Pasaje, C. F. A., Rubiano, K., Striepen, J., Abla, N., Berning, L., Bolscher, J. M., Demarta-Gatsi, C., Henderson, R. W. M., Huijs, T., Koolen, K. M. J., Tumwebaze, P. K., Yeo, T., Aguiar, A. C. C., Angulo-Barturen, I., ... Dechering, K. J. (2022). Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. Nature communications, 13(1), Article 2158. https://doi.org/10.1038/s41467-022-29688-5

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title = "Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183",

abstract = "Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.",

author = "{de Vries}, {Laura E.} and Jansen, {Patrick A.M.} and Catalina Barcelo and Justin Munro and Verhoef, {Julie M.J.} and Pasaje, {Charisse Flerida A.} and Kelly Rubiano and Josefine Striepen and Nada Abla and Luuk Berning and Bolscher, {Judith M.} and Claudia Demarta-Gatsi and Henderson, {Rob W.M.} and Tonnie Huijs and Koolen, {Karin M.J.} and Tumwebaze, {Patrick K.} and Tomas Yeo and Aguiar, {Anna C.C.} and I{\~n}igo Angulo-Barturen and Alisje Churchyard and Jake Baum and Fern{\'a}ndez, {Benigno Crespo} and Aline Fuchs and Gamo, {Francisco Javier} and Guido, {Rafael V.C.} and Jim{\'e}nez-Diaz, {Mar{\'i}a Bel{\'e}n} and Pereira, {Dhelio B.} and Rosemary Rochford and Camille Roesch and Sanz, {Laura M.} and Graham Trevitt and Benoit Witkowski and Sergio Wittlin and Cooper, {Roland A.} and Rosenthal, {Philip J.} and Sauerwein, {Robert W.} and Joost Schalkwijk and Hermkens, {Pedro H.H.} and Bonnert, {Roger V.} and Brice Campo and Fidock, {David A.} and Manuel Llin{\'a}s and Niles, {Jacquin C.} and Kooij, {Taco W.A.} and Dechering, {Koen J.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-29688-5",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

de Vries, LE, Jansen, PAM, Barcelo, C, Munro, J, Verhoef, JMJ, Pasaje, CFA, Rubiano, K, Striepen, J, Abla, N, Berning, L, Bolscher, JM, Demarta-Gatsi, C, Henderson, RWM, Huijs, T, Koolen, KMJ, Tumwebaze, PK, Yeo, T, Aguiar, ACC, Angulo-Barturen, I, Churchyard, A, Baum, J, Fernández, BC, Fuchs, A, Gamo, FJ, Guido, RVC, Jiménez-Diaz, MB, Pereira, DB, Rochford, R, Roesch, C, Sanz, LM, Trevitt, G, Witkowski, B, Wittlin, S, Cooper, RA, Rosenthal, PJ, Sauerwein, RW, Schalkwijk, J, Hermkens, PHH, Bonnert, RV, Campo, B, Fidock, DA, Llinás, M, Niles, JC, Kooij, TWA & Dechering, KJ 2022, 'Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183', Nature communications, vol. 13, no. 1, 2158. https://doi.org/10.1038/s41467-022-29688-5

TY - JOUR

T1 - Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

AU - de Vries, Laura E.

AU - Jansen, Patrick A.M.

AU - Barcelo, Catalina

AU - Munro, Justin

AU - Verhoef, Julie M.J.

AU - Pasaje, Charisse Flerida A.

AU - Rubiano, Kelly

AU - Striepen, Josefine

AU - Abla, Nada

AU - Berning, Luuk

AU - Bolscher, Judith M.

AU - Demarta-Gatsi, Claudia

AU - Henderson, Rob W.M.

AU - Huijs, Tonnie

AU - Koolen, Karin M.J.

AU - Tumwebaze, Patrick K.

AU - Yeo, Tomas

AU - Aguiar, Anna C.C.

AU - Angulo-Barturen, Iñigo

AU - Churchyard, Alisje

AU - Baum, Jake

AU - Fernández, Benigno Crespo

AU - Fuchs, Aline

AU - Gamo, Francisco Javier

AU - Guido, Rafael V.C.

AU - Jiménez-Diaz, María Belén

AU - Pereira, Dhelio B.

AU - Rochford, Rosemary

AU - Roesch, Camille

AU - Sanz, Laura M.

AU - Trevitt, Graham

AU - Witkowski, Benoit

AU - Wittlin, Sergio

AU - Cooper, Roland A.

AU - Rosenthal, Philip J.

AU - Sauerwein, Robert W.

AU - Schalkwijk, Joost

AU - Hermkens, Pedro H.H.

AU - Bonnert, Roger V.

AU - Campo, Brice

AU - Fidock, David A.

AU - Llinás, Manuel

AU - Niles, Jacquin C.

AU - Kooij, Taco W.A.

AU - Dechering, Koen J.

PY - 2022/12

Y1 - 2022/12

N2 - Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.

AB - Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.

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UR - http://www.scopus.com/inward/citedby.url?scp=85128451166&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-29688-5

DO - 10.1038/s41467-022-29688-5

M3 - Article

C2 - 35444200

AN - SCOPUS:85128451166

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2158

ER -

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Abstract

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