Anticoccidial drug discovery: Approaches towards the identification of novel chemotherapeutic agents

Jennifer W Anderson1, Tesfaye Biftu2, Christine Brown3, Robert G k Donald1, Anne Gurnett1, Penny Sue Leavitt1, John Mathew3, Bakela Nare1, Dennis Schmatz1, Tamas Tamas1, Donald Thompson3, Tanya Zhong1 and Paul Liberator1

Departments of Human and Animal Infectious Disease Research1, Medicinal Chemistry2 and Pharmacology3, Merck & Co., Inc. Rahway, New Jersey USA
paul_liberator@merck.com


New chemotherapeutic agents that efficiently control avian coccidiosis have not been introduced to the poultry industry for three decades. Despite the creative use of shuttle programs, the biological cycling of Eimeria parasites and the high density housing that is typical for poultry operations today have predisposed the industry to drug resistance. The identification of novel antiparasitic agents has become essential for continued chemotherapeutic control of avian coccidiosis. A new anticoccidial agent must have the following features: (i) novel molecular target to minimize the potential for cross-resistance in field isolates, (ii) minimal resistance induction potential, (iii) potent spectrum of activity against all Eimeria spp. commonly encountered in the field, (iv) an acceptable therapeutic index without genotoxicity, (v) no tissue residue issues, and (vi) simple chemistry to be able to provide sufficient bulk material while meeting the stringent economic requirements imposed by the industry.

The list of potential drug targets promises to grow as a result of the availability and comparative analysis of apicomplexan parasite genomes, including that of E. tenella. Until this time, our discovery efforts have been based in empiric screens, scoring for inhibition of parasite growth in cell culture. The ability to conduct “clinical” efficacy studies early in the program using a minimal amount of a compound with empiric whole cell in vitro activity is an enormous advantage for anticoccidial discovery. Conventional biochemical tools are used to help identify potential targets or pathways responsible for the antiparasitic activity of empiric hits. Critically important to the discovery process, and in conjunction with chemical validation, is genetic validation of the molecular target. Using T. gondii as a model parasite, demonstration that a potential gene target is essential rather than functionally redundant or dispensable in the parasite life cycle is required to warrant medicinal chemistry involvement. Synthetic modification of the primary hit to develop suitable pharmacokinetic and safety properties, with a focus on simple inexpensive chemistry then follows. In this presentation the identification of parasite cGMP-dependent protein kinase (PKG) as a molecular target and optimization of PKG inhibitors will be used to illustrate the discovery process.