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

Abstract

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.

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

“…This is particularly important for diseases in developing countries, for which research funds are limited (8). Here, we provide evidence in support of the repurposing of salinomycin and/or other ionophores as antimalarial and transmission-blocking agents.…”

“…Successful repositioning of drugs significantly benefits the clinical development pipeline in term of costs and time (8). Here, we demonstrated the antimalarial and transmission-blocking activities of a specific class of compounds, the monovalent ionophores (i.e., salinomycin, monensin, and nigericin), polyether antibiotics that are used in several countries as anticoccidial agents in poultry.…”

Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

“…29 Repositioning of existing drugs is seen as a possible general strategy for the development of new antimalarials, even though the challenges of such an approach are clear. 30 There has been much recent discussion of the need for “Open Innovation”, a term with a nebulous definition but typically describing a range of ideas from the sharing of data in a precompetitive environment through to competitions that allow organizations to bring in the best external ideas to complement in-house research but for which there is no requirement for any collaboration. 31 …”

One-pot synthesis and negative ion mass spectrometric investigation of a densely functionalized cinnoline

“…1). 1 Historically, they have been based on their natural product counterparts and among these, quinolines, such as quinine 1, have continued to feature prominently in antimalarial drug research. 2 Additionally, there are acridine drugs, such as quinacrine 2, originating from unnatural vat dyes which were themselves used to stain and quantify parasites within mammalian cells.…”