Dose-fractionation studies of a <i>Plasmodium</i> phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria-Reference-Cited by-同舟云学术

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

Published:2024-08-28 Issue: Volume: Page:
ISSN:0066-4804
Container-title:Antimicrobial Agents and Chemotherapy
language:en
Short-container-title:Antimicrob Agents Chemother

Author:

Gibhard Liezl¹^ORCID,Njoroge Mathew¹,Mulubwa Mwila¹,Lawrence Nina¹,Smith Dennis²,Duffy James³,Le Manach Claire¹,Brunschwig Christel¹,Taylor Dale¹,van der Westhuyzen Renier¹,Street Leslie J.¹,Basarab Gregory S.¹^ORCID,Chibale Kelly¹⁴

Affiliation:

1. Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa

2. Independent Researcher, Kent, United Kingdom

3. Medicines for Malaria Venture, ICC, Geneva, Switzerland

4. 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

Abstract

ABSTRACT 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.

Funder

Technology Innovation Agency

Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council

Medicines for Malaria Venture

Neville Isdell

South African National Research Foundation

Publisher

American Society for Microbiology

Link

https://journals.asm.org/doi/pdf/10.1128/aac.00842-24

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