Thompson DP et al. (1997) Parasitology "Prospects for rational approaches to anthelmintic discovery."

Klein RD, Thompson DP, Geary TG

[Parasitology, 1997]

Rational approaches to anthelmintic discovery include the design of screens for compounds directed at specific proteins in helminths that are pharmacologically distinguishable from their vertebrate homologues. The existence of several anthelmintics that selectively target the neuromusculature of helminths (e.g. levamisole, ivermectin, praziquantel, metrifonate), together with recent basic research in helminth physiology, have contributed to the recognition that neurobiology distinguishes these organisms from their vertebrate hosts. In this survey, we focus on mechanism-based screening and its application to anthelmintic discovery, with particular emphasis on targets in the neuromusculature of helminths. Few of these proteins have been exploited in chemotherapy. However, recent studies in comparative pharmacology and molecular biology, including the C. elegans genome project, have provided insights on potential new targets and, in some cases, molecular probes useful for their incorporation in mechanism-based screens.

Geary TG et al. (1999) Int J Parasitol "Mechanism-based screening: discovery of the next generation of anthelmintics depends upon more basic research."

Thompson DP, Klein RD, Geary TG

[Int J Parasitol, 1999]

The therapeutic arsenal for the control of helminth infections contains only a few chemical classes. The development and spread of resistance has eroded the utility of most currently available anthelmintics, at least for some indications, and is a constant threat to further reduce the options for treatment. Discovery and development of novel anthelmintic templates is strategically necessary to preserve the economic and health advantages now gained through chemotherapy. As the costs of development escalate, the question of how best to discover new drugs becomes paramount. Although random screening in infected animals led to the discovery of all currently available anthelmintics, cost constraints and a perception of diminishing returns require new approaches. Taking a cue from drug discovery programmes for human illnesses, we suggest that mechanism-based screening will provide the next generation of anthelmintic molecules. Critical to success in this venture will be the exploitation of the Caenorhabditis elegans genome through bioinformatics and genetic technologies. The greatest obstacle to success in this endeavour is the paucity of information available about the molecular physiology of helminths, making the choice of a discovery target a risky proposition.

Geary TG et al. (1995) Int J Parasitol "The pharmacology of FMRFamide-related neuropeptides in nematodes: new opportunities for rational anthelmintic discovery?"

Klein RD, Friedman AR, Winterrowd CA, Geary TG, Davis JP, Bowman JW, Thompson DP, Maule AG

[Int J Parasitol, 1995]

The chemotherapeutic control of helminth parasites is compromised by the limited number of classes of anthelmintic drugs. Discovery of novel anthelmintics is impeded by the lack of novel screening technologies that overcome the difficulties inherent in screens based on whole organism toxicity. The development and implementation of mechanism-based screens for new anthelmintics offers great promise for the revitalization of antiparasitic drug discovery. However, mechanism-based screens must be based on a thorough understanding of the proteins or processes that offer the best chance for selective chemotherapeutic intervention. Basic research on the characterization of nematode FMRF amide-related peptides (FaRPs) has revealed that these peptides are ubiquitously distributed in helminths. Chemical identification of a number of nematode FaRPs has been achieved, and these peptides have potent and profound effects on the nematode neuromuscular system. Physiological processes mediated by nematode FaRPs (and other helminth neuropeptides) offer potential targets for the discovery of novel anthelmintics.