Background: Repositioning 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. Methods. Molecules 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. Results: Of 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. Conclusions: Repositioning 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.
|State||Published - Apr 14 2014|
Bibliographical noteFunding Information:
This work was supported by the Medicines Malaria Venture, St Jude Children's Research Hospital, GlaxoSmithKline Plc and Pfizer Inc.
Thanks to Steve Trusko at Cephalon Inc, West Chester, PA, USA for providing compounds for testing. Thanks to Thierry Diagana at Novartis for providing PSC-833 compound for testing at GSK Tres Cantos. We thank the staff at MMV for the critical discussion and contributions throughout the project and the funding organizations for their support of MMV. RKG, WAG and JAC acknowledge the financial support of the American Lebanese Syrian Associated Charities (ALSAC) and NIH (AI075517 and AI090662). The authors are indebted to María Belén Jiménez-Díaz, Sara Viera, Helen Garuti, Noemí Magán Marchal, Vanesa Gómez, Teresa Mulet, Javier Ibáñez, María Santos Martínez, Leticia Huertas, Maria Jose Lafuente, Sara Prats, and Jaume Vidal at GSK for performing the in vivo experiments in P. falciparum-humanized mouse model. We thank Dr Leonard D Shultz and The Jackson Laboratory for providing access to NOD-scidIL-2Rγnull mice through their collaboration with GlaxoSmithKline-Tres Cantos Medicines Development Campus. Thanks to Achyut Sinha, Bala Subramanian, Suresh Solapure, the DMPK and compound management teams at AstraZeneca for their various invaluable contributions to this project. Naomi Richardson of Magenta Communications Ltd provided writing and editorial assistance on this paper and was funded by Medicines for Malaria Venture.
- Anti-malarial drugs
- Candidate drug re-profiling
- Drug repositioning
- Plasmodium berghei
- Plasmodium falciparum
- in vitro
- in vivo
ASJC Scopus subject areas
- Infectious Diseases