The challenges of developing novel antiparasitic drugs

Abstract

Only a few novel classes of antiparasitic drugs have emerged over the last few decades, reflecting the difficulties associated with bringing a safe, effective molecule to market. In recent years, the screening paradigm has shifted from empirical whole parasite screening towards mechanism-based high throughput screening. This approach requires investment in molecular parasitology and in understanding the basic biology of parasites, as well as requiring considerable investment in an infrastructure for screening. Add to this the fact that the drug discovery process is iterative with high attrition, the Animal Health industry by necessity must focus on discovering medicines for diseases, which will deliver a return on investment. In recent years the rapid progression of genomics has unlocked a plethora of tools for target identification, validation and screening, revolutionising mechanism-based screening for antiparasitic drug discovery. The challenge still remains; however, to identify novel chemical entities with the properties required to deliver a safe, effective antiparasitic drug.

Progress and challenges in the discovery of macrofilaricidal drugs

“…This is particularly the case for hits derived from whole-organism screens of random compound collections; it is quite easy to identify compounds that kill nematodes in culture at a concentration of 10 µM (a standard screening point), but progressing such hits to true leads (activity at nontoxic doses against parasites in an animal) has proven to be remarkably challenging. This has been the experience even in the animal health industry, which has screened millions of compounds and extracts against nematodes, especially C. elegans, in culture, with very few new products to show for the effort [16,76]. It must be acknowledged that at least the prototype of every commercially available anthelmintic, including the newer classes, was discovered in animals infected with parasites.…”

“…The relatively low throughput tolerated in whole nematode screens that employ parasites means that compound collections should be selected prior to assay; selection can be based on activity against related organisms (other nematodes, helminths or invertebrates) or on the basis of mechanism of action (e.g., collections of kinase inhibitors or G protein-coupled receptor ligands) [76,84,[97][98][99]. This strategy enables follow-up testing in labor-intensive secondary screens because of the intrinsic chemical-pharmacological merit embodied in selected libraries compared with truly random libraries.…”

Synergism between ivermectin and the tyrosine kinase/ P -glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

“…Given the time and cost of developing new drugs (Woods and Williams, 2007), there is a need to manage the use of the existing drugs to preserve their usefulness for as long as possible. Means to achieve this include the elucidation of resistance mechanisms in order to develop resistance diagnostics (Kotze et al, 2014), as well as the use of compounds that can act to inhibit resistance mechanisms, and hence restore anthelmintic susceptibility to resistant worms (for example Lespine et al, 2012).…”

New Ventures in the Genotoxic and Cytotoxic Effects of Macrocyclic Lactones, Abamectin and Ivermectin

“…Employing mice infected with the nematode parasite Nematospiroides dubius , the new animal model immediately showed the presence of an exceptional anthelmintic property [Burg and Stapley, 1989]. Afterwards, the active anthelmintic principle was isolated in 1975 and was named Avermectin [Burg et al, 1979;Egerton et al, 1979;Miller et al, 1979;Woods and Williams, 2007;Ŏmura, 2008]. The Avermectins are indeed 16-membered macrocyclic polyketides which possess excellent biocidal activity with not only a good potency and broad spectrum of activity against a variety of nematode, insect and arachnid parasites (without antibacterial and antifungal activity) but also with a low level of side-effects on the host organism in both humans and animals .…”