Antiparasitics are a class of chemicals which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, ectoparasites, parasitic fungi, and protozoa, among others. Antiparasitics target the parasitic agents of the infections by destroying them or inhibiting their growth; they are usually effective against a limited number of parasites within a particular class. Antiparasitics are one of the antimicrobial drugs which include antibiotics that target bacteria, and antifungals that target fungi.
Screening for antiparasitic drugs as a scientific exercise can be traced to the early work of Ehrlich, who screened a collection of synthetic dyes for trypanocidal activity in mice with the aim of allowing the importation of European horses and cattle into the African colonies of Germany prior to 1900. This was perhaps the first example of a screen of a collection of chemicals for any therapeutic indication; Ehrlich’s efforts at drug discovery seem to have begun with a veterinary parasite as target, but led to the introduction of the first anti-infective drugs for use in humans. Thus, the process by which drugs introduced into veterinary practice for parasite control were adopted for use in humans has a long history.
Special Challenges for Antiparasitic Drug Discovery in Animal Health
There are however some features of antiparasitic drug discovery which create a more demanding starting point for the animal health target-based approach. Foremost, is the goal to discover drugs against a wide spectrum of target organisms, often occupying different niches. Whereas human health drug discovery can focus on one target organism, the animal health industry seeks to cover species as diverse as flies, fleas, and ticks in the ectoparasitic field, as well as nematodes, trematodes, and cestodes in the endoparasitic field. The situation is complicated by the fact that the spectrum of patients includes fish, companion animals and livestock animals. Whilst the spectrum of patients poses a generic challenge for medicinal chemistry, the wide spectrum of target parasites demands a decision as to whether to select a representative target protein (e.g., an ion channel from D. melanogaster as the target for ticks, fleas, and flies) or to use orthologous targets from representative parasitic species to identify overlapping hits. In our experience, screening with parasitic targets increases the chance of identifying bioactive substances with the desired spectrum and allows rational decision making when it comes to lead optimization because parasitic on target activity can be correlated with parasitic in vivo activity.
Properties of a Valid Antiparasitic Screening Target
A valid antiparasitic screening target has to fulfill certain criteria: The target should be required for survival or fitness of the parasite in the relevant developmental stages. These would be the blood-sucking and reproducing stages for fleas and ticks and the larval and adult stages for pest flies. For endoparasites like nematodes the situation is similar in that late larval and adult stages are most important for fast-acting intervention. This criterion is critical for the success of a project as it can not be compensated for later in the drug development process. Equally important is the suitability of a target for HTS screening. Comparable to human health drug discovery, the assay repertoire spans ion channels, GPCRs, and enzymes. In human health drug discovery, only one high-throughput assay per target has to be established whereas the animal health situation requires that the targets of several representative parasitic species be cloned and functionally expressed.
Another criterion is the extent to which a given drug target is prone to the development of drug resistance. This aspect is of particular importance as the development of resistance against current antiparasitics is one of the driving forces of the search for new chemical classes or modes of action. There are some examples in the literature where target site resistance could be induced under controlled conditions. Furthermore, genetic prediction tools for resistance development have been established.
Also of importance for the success of a project are whether a target function is rate limiting in its pathway, whether there is redundancy, and whether the target turnover allows inhibition over a reasonable time period. Finally, there are criteria such as selectivity and structural information which can improve the success probability but are too rare to apply as a strict rule.
Selzer, P. M. (Ed.). (2009). Antiparasitic and antibacterial drug discovery: from molecular targets to drug candidates (Vol. 1). John Wiley & Sons.