Repositioning: the fast track to new anti-malarial medicines?

Malaria Journal

Research

Sowmya Bharath¹  Pavithra Viswanath¹  Balachandra Bandodkar¹  Nikhil Rautela¹  Julie Clark²  Michele Connelly²  R Kiplin Guy²  Sandra Duffy³  Vicky M Avery³  Santiago Ferrer-Bazaga⁴  Francisco Javier Gamo-Benito⁴  Iñigo Angulo-Barturen⁴  Tanya Parkinson⁵  Timothy Wells⁶  Julie Lotharius⁶  Jörg J Möhrle⁶ 

[1] AstraZeneca India Pvt Ltd, Bellary Road, Hebbal, Bangalore, India;Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, TN, USA;Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Australia;Diseases of the Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Tres Cantos, Spain;Independent Consultant, Canterbury, UK;Medicines for Malaria Venture (MMV), PO Box 1826, 20 rte de Pré-Bois, 1215, Geneva 15, Switzerland;

关键词: Malaria;    Anti-malarial drugs;    Drug repositioning;    in vitro;    in vivo;    Plasmodium falciparum;    Plasmodium berghei;    Candidate drug re-profiling;   

DOI  :  10.1186/1475-2875-13-143

 received in 2014-02-05, accepted in 2014-03-23,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundRepositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages.MethodsMolecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [3H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4’,6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low μM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D70087/N9 huSCID ‘humanized’ mouse model.ResultsOf the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model.ConclusionsRepositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at μM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.

【 授权许可】

Unknown   
© Lotharius et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.