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 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 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

Menzies School of Health Research

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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.

Original language	English
Article number	eabg6013
Pages (from-to)	1-14
Number of pages	14
Journal	Science Translational Medicine
Volume	13
Issue number	603
DOIs	https://doi.org/10.1126/scitranslmed.abg6013
Publication status	Published - 21 Jul 2021

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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. Science Translational Medicine, 13(603), 1-14. [eabg6013]. https://doi.org/10.1126/scitranslmed.abg6013

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

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.",

author = "Murithi, {James M.} and C{\'e}cile Pascal and Jade Bath and Xavier Boulenc and Gn{\"a}dig, {Nina F.} and Pasaje, {Charisse Flerida A.} and Kelly Rubiano and Tomas Yeo and Sachel Mok and Sylvie Klieber and Paul Desert and Jim{\'e}nez-D{\'i}az, {Mar{\'i}a Bel{\'e}n} and Jutta Marfurt and M{\'e}lanie Rouillier and Cherkaoui-Rbati, {Mohammed H.} and Nathalie Gobeau and Sergio Wittlin and Uhlemann, {Anne Catrin} and Price, {Ric N.} and Grennady Wirjanata and Rintis Noviyanti and Patrick Tumwebaze and Cooper, {Roland A.} and Rosenthal, {Philip J.} and Sanz, {Laura M.} and Gamo, {Francisco Javier} and Jayan Joseph and Shivendra Singh and Sridevi Bashyam and Augereau, {Jean Michel} and Elie Giraud and Tanguy Bozec and Thierry Vermat and Gilles Tuffal and Guillon, {Jean Michel} and J{\'e}r{\^o}me Menegotto and Laurent Sall{\'e} and Guillaume Louit and Cabanis, {Marie Jos{\'e}} and Nicolas, {Marie Fran{\c c}oise} and Michel Doubovetzky and Rita Merino and Nadir Bessila and I{\~n}igo Angulo-Barturen and Delphine Baud and Lidiya Bebrevska and Fanny Escudi{\'e} and Niles, {Jacquin C.} and Benjamin Blasco and Simon Campbell and Gilles Courtemanche and Laurent Fraisse and Alain Pellet and Fidock, {David A.} and Didier Leroy",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine",

year = "2021",

month = jul,

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doi = "10.1126/scitranslmed.abg6013",

language = "English",

volume = "13",

pages = "1--14",

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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, AC, Price, RN, Wirjanata, G, Noviyanti, R, Tumwebaze, P, Cooper, RA, Rosenthal, PJ, Sanz, LM, Gamo, FJ, Joseph, J, Singh, S, Bashyam, S, Augereau, JM, Giraud, E, Bozec, T, Vermat, T, Tuffal, G, Guillon, JM, Menegotto, J, Sallé, L, Louit, G, Cabanis, MJ, 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', Science Translational Medicine, vol. 13, no. 603, eabg6013, pp. 1-14. https://doi.org/10.1126/scitranslmed.abg6013

TY - JOUR

T1 - The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

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

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

N1 - Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

PY - 2021/7/21

Y1 - 2021/7/21

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.

UR - http://www.scopus.com/inward/record.url?scp=85112546003&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.abg6013

DO - 10.1126/scitranslmed.abg6013

M3 - Article

C2 - 34290058

AN - SCOPUS:85112546003

VL - 13

SP - 1

EP - 14

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 603

M1 - eabg6013

ER -

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

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