Dose-fractionation studies of a Plasmodium phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.

Autor:	Gibhard L; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Njoroge M; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Mulubwa M; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Lawrence N; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Smith D; Independent Researcher, Kent, United Kingdom., Duffy J; Medicines for Malaria Venture, ICC, Geneva, Switzerland., Le Manach C; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Brunschwig C; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Taylor D; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., van der Westhuyzen R; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Street LJ; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Basarab GS; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa., Chibale K; Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa.; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Oct 08; Vol. 68 (10), pp. e0084224. Date of Electronic Publication: 2024 Aug 28.
DOI:	10.1128/aac.00842-24
Abstrakt:	UCT594 is a 2-aminopyrazine carboxylic acid Plasmodium phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the Plasmodium falciparum NSG mouse model to determine the PK/PD indices of UCT594, using the in vivo minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the P. falciparum -infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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