Plenary
Lectures
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.