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.