The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

James M Murithi; Cécile Pascal; Jade Bath; Xavier Boulenc; Nina F. Gnädig; Charisse Flerida A. Pasaje; Kelly Rubiano; Tomas Yeo; Sachel Mok; Sylvie Klieber; Paul Desert; María Belén Jiménez-Díaz; Jutta Marfurt; Mélanie Rouillier; Mohammed H. Cherkaoui-Rbati; Nathalie Gobeau; Sergio Wittlin; Anne-Catrin Uhlemann; Ric N. Price; Grennady Wirjanata; Rintis Noviyanti; Patrick K. Tumwebaze; Roland A. Cooper; Philip J. Rosenthal; Laura M. Sanz; Francisco-Javier Gamo; Jayan Joseph; Shivendra Singh; Sridevi Bashyam; Jean Michel Augereau; Elie Giraud; Tanguy Bozec; Thierry Vermat; Gilles Tuffal; Jean-Michel Guillon; Jérôme Menegotto; Laurent Sallé; Guillaume Louit; Marie-José Cabanis; Marie Françoise Nicolas; Michel Doubovetzky; Rita Merino; Nadir Bessila; Iñigo Angulo-Barturen; Delphine Baud; Lidiya Bebrevska; Fanny Escudié; Jacquin C Niles; Benjamin Blasco; Simon Campbell; Gilles Courtemanche; Laurent Fraisse; Alain Pellet; David A. Fidock; Didier Leroy

doi:10.1126/scitranslmed.abg6013

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

James M Murithi, Cécile Pascal, Jade Bath, Xavier Boulenc, Nina F. Gnädig, Charisse Flerida A. Pasaje, Kelly Rubiano, Tomas Yeo, Sachel Mok, Sylvie Klieber, Paul Desert, María Belén Jiménez-Díaz, Jutta Marfurt, Mélanie Rouillier, Mohammed H. Cherkaoui-Rbati, Nathalie Gobeau, Sergio Wittlin, Anne-Catrin Uhlemann, Ric N. Price, Grennady WirjanataRintis Noviyanti, Patrick K. Tumwebaze, Roland A. Cooper, Philip J. Rosenthal, Laura M. Sanz, Francisco-Javier Gamo, Jayan Joseph, Shivendra Singh, Sridevi Bashyam, Jean Michel Augereau, Elie Giraud, Tanguy Bozec, Thierry Vermat, Gilles Tuffal, Jean-Michel Guillon, Jérôme Menegotto, Laurent Sallé, Guillaume Louit, Marie-José Cabanis, Marie Françoise Nicolas, Michel Doubovetzky, Rita Merino, Nadir Bessila, Iñigo Angulo-Barturen, Delphine Baud, Lidiya Bebrevska, Fanny Escudié, Jacquin C Niles, Benjamin Blasco, Simon Campbell, Gilles Courtemanche, Laurent Fraisse, Alain Pellet, David A. Fidock, Didier Leroy

Department of Natural Sciences and Mathematics

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

Abstract

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

Original language	American English
Article number	eabg6013
Journal	Default journal
Volume	13
Issue number	603
DOIs	https://doi.org/10.1126/scitranslmed.abg6013
State	Published - Jul 21 2021

Funding

Funders	Funder number
National Institute of Allergy and Infectious Diseases	R01AI109023

Keywords

Animals
Antimalarials
Endocytosis
Malaria
Falciparum
Parasites
Plasmodium falciparum

Disciplines

Parasitic Diseases
Life Sciences

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10.1126/scitranslmed.abg6013

The antimalarial MMV688533 provides potential for single-dose curFinal published version, 1.07 MBLicense: Unspecified
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Murithi, J. M., Pascal, C., Bath, J., Boulenc, X., Gnädig, N. F., Pasaje, C. F. A., Rubiano, K., Yeo, T., Mok, S., Klieber, S., Desert, P., Jiménez-Díaz, M. B., Marfurt, J., Rouillier, M., Cherkaoui-Rbati, M. H., Gobeau, N., Wittlin, S., Uhlemann, A.-C., Price, R. N., ... Leroy, D. (2021). The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance. Default journal, 13(603), Article eabg6013. https://doi.org/10.1126/scitranslmed.abg6013

Murithi, JM, Pascal, C, Bath, J, Boulenc, X, Gnädig, NF, Pasaje, CFA, Rubiano, K, Yeo, T, Mok, S, Klieber, S, Desert, P, Jiménez-Díaz, MB, Marfurt, J, Rouillier, M, Cherkaoui-Rbati, MH, Gobeau, N, Wittlin, S, Uhlemann, A-C, Price, RN, Wirjanata, G, Noviyanti, R, Tumwebaze, PK, Cooper, RA, Rosenthal, PJ, Sanz, LM, Gamo, F-J, Joseph, J, Singh, S, Bashyam, S, Augereau, JM, Giraud, E, Bozec, T, Vermat, T, Tuffal, G, Guillon, J-M, Menegotto, J, Sallé, L, Louit, G, Cabanis, M-J, Nicolas, MF, Doubovetzky, M, Merino, R, Bessila, N, Angulo-Barturen, I, Baud, D, Bebrevska, L, Escudié, F, Niles, JC, Blasco, B, Campbell, S, Courtemanche, G, Fraisse, L, Pellet, A, Fidock, DA & Leroy, D 2021, 'The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance', Default journal, vol. 13, no. 603, eabg6013. https://doi.org/10.1126/scitranslmed.abg6013

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abstract = "The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.",

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AU - Murithi, James M

AU - Pascal, Cécile

AU - Bath, Jade

AU - Boulenc, Xavier

AU - Gnädig, Nina F.

AU - Pasaje, Charisse Flerida A.

AU - Rubiano, Kelly

AU - Yeo, Tomas

AU - Mok, Sachel

AU - Klieber, Sylvie

AU - Desert, Paul

AU - Jiménez-Díaz, María Belén

AU - Marfurt, Jutta

AU - Rouillier, Mélanie

AU - Cherkaoui-Rbati, Mohammed H.

AU - Gobeau, Nathalie

AU - Wittlin, Sergio

AU - Uhlemann, Anne-Catrin

AU - Price, Ric N.

AU - Wirjanata, Grennady

AU - Noviyanti, Rintis

AU - Tumwebaze, Patrick K.

AU - Cooper, Roland A.

AU - Rosenthal, Philip J.

AU - Sanz, Laura M.

AU - Gamo, Francisco-Javier

AU - Joseph, Jayan

AU - Singh, Shivendra

AU - Bashyam, Sridevi

AU - Augereau, Jean Michel

AU - Giraud, Elie

AU - Bozec, Tanguy

AU - Vermat, Thierry

AU - Tuffal, Gilles

AU - Guillon, Jean-Michel

AU - Menegotto, Jérôme

AU - Sallé, Laurent

AU - Louit, Guillaume

AU - Cabanis, Marie-José

AU - Nicolas, Marie Françoise

AU - Doubovetzky, Michel

AU - Merino, Rita

AU - Bessila, Nadir

AU - Angulo-Barturen, Iñigo

AU - Baud, Delphine

AU - Bebrevska, Lidiya

AU - Escudié, Fanny

AU - Niles, Jacquin C

AU - Blasco, Benjamin

AU - Campbell, Simon

AU - Courtemanche, Gilles

AU - Fraisse, Laurent

AU - Pellet, Alain

AU - Fidock, David A.

AU - Leroy, Didier

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N2 - The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

AB - The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

KW - Animals

KW - Antimalarials

KW - Endocytosis

KW - Malaria

KW - Falciparum

KW - Parasites

KW - Plasmodium falciparum

UR - https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/93

UR - https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/83

U2 - 10.1126/scitranslmed.abg6013

DO - 10.1126/scitranslmed.abg6013

M3 - Article

C2 - 34290058

VL - 13

JO - Default journal

JF - Default journal

IS - 603

M1 - eabg6013

ER -

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

Abstract

Funding

Keywords

Disciplines

Access to Document

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