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.
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 (PZQ), 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, parasitic worms causing schistosomiasis. We will develop unique inhibitors of a novel target in these parasitic organisms, histone deacetylase 8, as potential treatment for schistosomiasis.