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

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

Department of Natural Sciences and Mathematics

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

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	American English
Article number	2158
Pages (from-to)	2158
Journal	Default journal
Volume	13
Issue number	1
State	Published - Apr 20 2022

Funding

We gratefully acknowledge S. Mok for assistance with whole-genome sequencing analysis, C. Bioni for providing access to the laboratory for the Brazilian-field isolates ex vivo assessments, O. Byaruhanga, S. Orena, M. Okitwi and T. Katairo for assistance with ex vivo assays on fresh P. falciparum isolates in Uganda, S. Sax for technical assistance with the SCID mouse P. falciparum in vivo efficacy studies performed at Swiss TPH. We thank D.F. Wirth, A.K. Lukens and R. Summers for pre-publication sharing of data and fruitful discussions. T. Spielmann is acknowledged for providing the plasmid SLI-TGD. We also thank the Huck Institutes of Life Sciences Metabolomics Core Facility at Penn State University. LEdV was supported by a PhD fellowship from the Radboud Institute for Molecular Life Sciences, Radboudumc (RIMLS015-010), JMJV by an individual Radboudumc Master-PhD grant, TWAK by the Netherlands Organisation for Scientific Research (NWO-VIDI 864.13.009), JM by an NIH training grant (T32 DK120509), ML by the Bill & Melinda Gates Foundation (OPP1054480), JCN by the Bill & Melinda Gates Foundation (OPP1162467 and OPP1054480), JB by an Investigator Award from Wellcome (100993/Z/13/Z), DAF by the Medicines for Malaria Venture (RD/08/0015), the Department of Defense (W81XWH1910086) and the NIH (R01 AI109023), RVCG by Sao Paulo Research Foundation (FAPESP - CEPID grant 2013/07600-3 and 2020/12904-5), and ACCA by an Investigator Award from FAPESP (2019/19708-0). DGFA screening was supported by the Medicines for Malaria Venture (RD-08-2800, award to JB and AC), clinical field isolates experiments in Brazil were funded through ongoing MMV support, project RD-16-1066 (RVCG, ACCA), ex vivo studies in Uganda were supported by the NIH (R01AI139179) and Medicines for Malaria Venture (RD/15/0001), the efficacy study on ACT-resistant isolates was supported by the Medicines for Malaria Venture. We further acknowledge support by MalDA (OPP1054480; PI Dr. E. Winzeler, UCSD). We gratefully acknowledge S. Mok for assistance with whole-genome sequencing analysis, C. Bioni for providing access to the laboratory for the Brazilian-field isolates ex vivo assessments, O. Byaruhanga, S. Orena, M. Okitwi and T. Katairo for assistance with ex vivo assays on fresh P. falciparum isolates in Uganda, S. Sax for technical assistance with the SCID mouse P. falciparum in vivo efficacy studies performed at Swiss TPH. We thank D.F. Wirth, A.K. Lukens and R. Summers for pre-publication sharing of data and fruitful discussions. T. Spielmann is acknowledged for providing the plasmid SLI-TGD. We also thank the Huck Institutes of Life Sciences Metabolomics Core Facility at Penn State University. LEdV was supported by a PhD fellowship from the Radboud Institute for Molecular Life Sciences, Radboudumc (RIMLS015-010), JMJV by an individual Radboudumc Master-PhD grant, TWAK by the Netherlands Organisation for Scientific Research (NWO-VIDI 864.13.009), JM by an NIH training grant (T32 DK120509), ML by the Bill & Melinda Gates Foundation (OPP1054480), JCN by the Bill & Melinda Gates Foundation (OPP1162467 and OPP1054480), JB by an Investigator Award from Wellcome (100993/Z/13/Z), DAF by the Medicines for Malaria Venture (RD/08/0015), the Department of Defense (W81XWH1910086) and the NIH (R01 AI109023), RVCG by Sao Paulo Research Foundation (FAPESP - CEPID grant 2013/07600-3 and 2020/12904-5), and ACCA by an Investigator Award from FAPESP (2019/19708-0). DGFA screening was supported by the Medicines for Malaria Venture (RD-08-2800, award to JB and AC), clinical field isolates experiments in Brazil were funded through ongoing MMV support, project RD-16-1066 (RVCG, ACCA), ex vivo studies in Uganda were supported by the NIH (R01AI139179) and Medicines for Malaria Venture (RD/15/0001), the efficacy study on ACT-resistant isolates was supported by the Medicines for Malaria Venture. We further acknowledge support by MalDA (OPP1054480; PI Dr. E. Winzeler, UCSD).

Funders	Funder number
MalDA
NWO-VIDI	864.13.009
Radboud Institute for Molecular Life Sciences	RIMLS015-010
National Institutes of Health	T32 DK120509
U.S. Department of Defense	W81XWH1910086, R01 AI109023
National Institute of Allergy and Infectious Diseases	R01AI139179
Bill and Melinda Gates Foundation	OPP1162467, OPP1054480
Pennsylvania State University
Wellcome Trust	100993/Z/13/Z
Fundação de Amparo à Pesquisa do Estado de São Paulo	2020/12904-5, 2013/07600-3
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Medicines for Malaria Venture	RD/08/0015
Asociación para la Conservación de la Cuenca Amazónica	RD-08-2800, RD/15/0001, 2019/19708-0, RD-16-1066

ASJC Scopus Subject Areas

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

Keywords

Animals
Antimalarials
Folic Acid Antagonists
Malaria
Falciparum
Vivax
Mice
Pantothenic Acid
Plasmodium falciparum
Rats

Disciplines

Parasitic Diseases

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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. Default journal, 13(1), 2158. Article 2158.

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, F-J, 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.', Default journal, vol. 13, no. 1, 2158, pp. 2158.

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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.",

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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

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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 - 2022/4/20

Y1 - 2022/4/20

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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KW - Antimalarials

KW - Folic Acid Antagonists

KW - Malaria

KW - Falciparum

KW - Vivax

KW - Mice

KW - Pantothenic Acid

KW - Plasmodium falciparum

KW - Rats

UR - https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/87

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VL - 13

SP - 2158

JO - Default journal

JF - Default journal

IS - 1

M1 - 2158

ER -

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Abstract

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

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