Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism.

Autor:	MacLeod AK; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Coquelin KS; Division of Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD2 4GD, United Kingdom., Huertas L; Global Health Research & Development, GlaxoSmithKline, Tres Cantos, Madrid 28760, Spain., Simeons FRC; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Riley J; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Casado P; Global Health Research & Development, GlaxoSmithKline, Tres Cantos, Madrid 28760, Spain., Guijarro L; Global Health Research & Development, GlaxoSmithKline, Tres Cantos, Madrid 28760, Spain., Casanueva R; Global Health Research & Development, GlaxoSmithKline, Tres Cantos, Madrid 28760, Spain., Frame L; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Pinto EG; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Ferguson L; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Duncan C; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Mutter N; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Shishikura Y; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom., Henderson CJ; Division of Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD2 4GD, United Kingdom., Cebrian D; Global Health Research & Development, GlaxoSmithKline, Tres Cantos, Madrid 28760, Spain., Wolf CR; Division of Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD2 4GD, United Kingdom., Read KD; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, United Kingdom.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Feb 13; Vol. 121 (7), pp. e2315069121. Date of Electronic Publication: 2024 Feb 05.
DOI:	10.1073/pnas.2315069121
Abstrakt:	A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis , Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery. Competing Interests: Competing interests statement:These authors are employees and/or shareholders in GlaxoSmithKline: A.K.M., L.H., P.C., L.G., R.C., D.C., and K.D.R. The other authors declare no competing interest. K.D.R. and C.R.W. are involved with the start-up company PhaSER Biomedical, which is making 8HUM mice available for both academic and commercial use.
Databáze:	MEDLINE
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