Schistosomiasis remains an important, neglected disease with more than 200 million people infected resulting in
200,000 deaths annually and untold chronic illness and disability. Only a single drug, praziquantel, is used for
schistosomiasis treatment and no second-line drugs are available. Reliance on a single drug to treat hundreds of
millions of people also raises concerns about the evolution of drug resistant schistosomes. Our long-term objective
is to develop novel approaches for the treatment of schistosomiasis utilizing novel therapeutic targets. Recent studies
by Pierce et al. have identified histone deacetylase 8 (smHDAC8) in Schistosoma mansoni parasites as a promising
target for development of novel therapeutic approaches to treat schistosomiasis. In S. mansoni, smHDAC8 is highly
expressed during all life cycle stages and it has been shown to be an essential and druggable protein. Several
synthetic smHDAC8 inhibitors were recently reported by the Pierce team. Although they were found active in vitro
against smHDAC8 and a few were also active against ex vivo worms, these compounds were only modestly selective
and in some cases not selective against class I and II human HDAC isoforms. The latter presents a serious problem
because these HDAC isoforms are involved in the regulation of a large variety of human enzymes and their inhibition
will result in unwanted toxicity. Clearly, novel, selective and safe smHDAC8 inhibitors are needed as both
pharmacological tools and as therapeutics for the treatment of schistosomiasis, a critical barrier in the field. Recently,
we developed a series of novel and highly potent and selective HDAC8 inhibitors with C1-substituted
tetrahydroisoquinoline (TIQ) chemotype. We hypothesize that we will be able to design potent, selective, and safe
inhibitors of smHDAC8 with schistosomicidal activity using compounds with TIQ-based chemotype, our short-term
goal of this R21 application. To achieve this goal, our aims are as follow: Aim 1: Identify novel inhibitors of smHDAC8
using iterative rounds of computer-aided molecular design, medicinal chemistry, and X-ray crystallographic structural
studies. Evaluate potency and selectivity for smHDAC8 vs human isoforms and establish important preliminary drug
metabolism and pharmacokinetic properties. Aim 2: Evaluate best candidates from Aim 1 for schistosomicidal activity
against larval, juvenile, and adult S. mansoni worms ex vivo and toxicity against human cells in vitro. To accomplish
these aims, an innovative collaboration of global experts with expertise in schistosome biochemistry and drug
discovery, computer-aided molecular design, medicinal chemistry, structural biology, and drug development has been
assembled. The varied and synergistic expertise of the team will facilitate overcoming critical barriers to drug
development. Completion of the project will result in novel inhibitors with: high selectivity for smHDAC8 over human
HDAC enzymes, druglike solubility and metabolic stability profiles in vitro, and in vitro activity against S. mansoni
worms. Although additional studies will be needed to further optimize potency of these compounds in vitro and in
animal models of the disease, evaluate the potential of these compounds for the treatment of S. haematobium and
S. japonicum, and optimize bioavailability and safety, the proposed studies are the essential first step.