Predicting Optimal Antimalarial Drug Combinations from a Standardized Plasmodium falciparum Humanized Mouse Model

Demarta‐Gatsi, Claudia; Andenmatten, Nicole; Jiménez-Díaz, María-Belén; Gobeau, Nathalie; Cherkaoui-Rabti, Mohammed H.; Fuchs, Aline; Díaz, Pablo; Berja, Sandra; Sánchez, Rebeca; Gómez, Hazel; Ruiz, Estíbaliz; Sainz, Paula; Salazar, E.; Gil-Merino, R.; Mendoza, Luis Manuel; Eguizábal, Cristina; Leroy, Didier; Moehrle, Joerg J.; Tornesi, Belén; Angulo-Barturen, Íñigo

doi:10.1128/aac.01574-22

Cited by 7 publications

(11 citation statements)

References 55 publications

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“…falciparum in vivo in the PfalchHuMouse model in comparable treatment regimens (ref Demarta-Gatsi et al AAC. DOI: 10.1128/aac.01574-22) (Figure D) . The total C min in the individuals treated with 7k were 51, 32, and 85 ng/mL for the individuals treated with UID, BID, and TID, respectively.…”

Section: Resultsmentioning

confidence: 95%

“…(d) PK/PD analysis of parasite killing in vivo induced by inhibitor 7k in comparison with chloroquine as a standard reference antimalarial drug. The data shown in the plot are the day of recrudescence (DoR) versus the total exposure in the blood of 7k of each individual mouse normalized by their respective individual parasite burdens as described . Data for Chloroquine are from historical data available at TAD for a set of PfalcHuMice treated p.o.…”

Section: Resultsmentioning

confidence: 99%

“…The PoC study allowed a preliminary PK/PD assessment of the antimalarial effect shown by 7k in the PfalcHuMouse model (Figure D). We addressed this assessment by analyzing the day of recrudescence (DoR) as a function of the total exposure in the blood of the drugs tested, as recently described . DoR is defined as the the day at which parasitemia reaches again the parasitemia at treatment inception after a transient decline in parasitemia and is used as a measurement of parasite killing induced by the drugs.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, inhibitor 7k was shown to be as potent as chloroquine killing (Figure 7D). 34 The total C min in the individuals treated with 7k were 51, 32, and 85 ng/mL for the individuals treated with UID, BID, and TID, respectively. A preliminary first estimate of the minimal parasiticidal concentration (MPC) of 85.3 ng/ mL could be calculated since the individual treated BID showed the maximum parasite clearance rate for the first 48 h. The PoC study allowed a preliminary PK/PD assessment of the antimalarial effect shown by 7k in the PfalcHuMouse model (Figure 7D).…”

Section: P Falciparum Growth Inhibition By Macrocycles Is Through The...mentioning

confidence: 89%

“…Therapeutic efficacy studies were performed at TAD using a standardized humanized mouse model of P. falciparum malaria 31 with modifications. 34 suspensions in RPMI 1640 medium, 25% (vol/vol) decomplemented human serum, and 3.1 mM hypoxanthine. The volume of injections was 1 and 0.7 mL for i.p.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity

Kovada,

Withers-Martinez,

Bobrovs

et al. 2023

J. Med. Chem.

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The Plasmodium falciparum aspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in in vitro parasite growth inhibition. Inhibitor 7k cleared blood-stage P. falciparum in a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound 7k represents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: P Falciparum Growth Inhibition By Macrocycles Is Through The...mentioning

confidence: 89%

Section: ■ Experimental Sectionmentioning

confidence: 99%

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