Challenges in drug discovery for novel antifilarials

Abstract

Control programmes are at present focused on the elimination of onchocerciasis and lymphatic filariasis as public health problems in countries where they are endemic. The availability of effective drugs used in combination (diethylcarbamazine, albendazole and ivermectin) has paved the way for the implementation of Mass Drug Administration (MDA) campaigns. Considerable progress in the implementation of MDA programmes had led to significant reductions in transmission and morbidity. However, new drugs are needed to overcome the threat of resistance to existing microfilaricides as well as to identify new macrofilaricides. This paper discusses the existing screening tools available for antifilarial drug discovery and efforts towards optimising their use through the Helminth Drug Initiative.

In VitroActivity of Geldanamycin Derivatives againstSchistosoma japonicumandBrugia malayi

“…For example, filaria killing studies are sometimes conducted in the presence of monkey kidney cell feeder layers up to a maximum of 120 hours, to control for the toxicity of test compounds [27]. However, in the case of most GA derivatives tested herein, (1) the lack of toxicity to human cells was already established, (2) the removal of serum from culture media permits longer in vitro culture as noted, up to 500 hours, and (3) such serum removal allows the evaluation of lipophilic compounds which can bind to albumin or other serum proteins and can obscure their inherent activity against filaria [28].…”

Synthesis and screening of substituted 1,4‐naphthoquinones (NPQs) as antifilarial agents

“…New antifilarial agents effective against adult filarial worms are required due to a dearth of new chemotherapeutic agents against filarial infections [Townson et al, 2007]. Of the 11 NPQs described in the present study, 7 showed macrofilaricidal activity with 9 (2-[(1,3-dimethylbutyl) amino] naphthalene-1, 4-dione) and 11 2-(4-methylpiperazin-1-yl) naphthalene-1,4-dione) showing maximum activity with ED 50 values of 0.91 and 1.2 mM, respectively, at 48-h incubation.…”

Integrated Dataset of Screening Hits against Multiple Neglected Disease Pathogens

“…It should be noted that the human pathogen for onchocerciasis is Onchocerca volvulus , but due to lack of a suitable in vitro assay or animal models for this pathogen, O. ochengi and lienalis , which are both animal pathogens, are used in the primary and secondary assays [16], [30].…”