The proposed research program reflects the research of the Principal Investigator, Michael P. Pollastri and his collaborator Dr. Robert Campbell at the Marine Biological Laboratory at Woods Hole in development of new compounds that hold promise as therapeutics for neglected diseases. In particular, since the genome for Trypanosoma brucei (the causative parasite for Human African Trypanosomiasis (HAT)) and T. cruzi (which causes Chagas disease) have been recently elucidated, a number of potentially therapeutically-relevant molecular targets have been identified. Moreover, several of these molecular targets display a moderate-to- high level of homology to orthologous human targets that have been well-explored in the biopharmaceutical industry for the treatment of human disease. The overarching goal of this project is to develop compounds that display a high level of inhibition of two trypanosomal phosphodiesterases, TbrPDEB1 and TbrPDEB2, enzymes that have been previously demonstrated by validation experiments (RNAi) to be required for parasite virulence. These parasitic enzymes show ~30-35% homology to, and the parasitic enzyme active sites are highly similar to those of the human enzymes. This project will seek to (1) purify and biochemically characterize the parasitic enzymes TbrPDEB1 and TbrPDEB2 to establish cell-free assays suitable for testing compounds for inhibitory activity during hit and lead optimization, (2) identify the best class of existing hPDE inhibitors for pursuit by medicinal chemistry optimization, and (3) optimize potent, selective inhibitor compounds that have in vivo activity (tested in collaboration with the World Health Organization) for the oral dosing and blood brain barrier penetration essential for activity in the most severe forms of HAT. This project is intended to deliver compounds suitable for consideration as clinical candidates. Recognizing that the optimization of compounds from screening for this purpose is a major gap in drug discovery for neglected diseases the investigators have designed the project to i) focus on meeting the clear Target Product Profile established by WHO for HAT and ii) promote and involve collaboration from experts from industry drug discovery, recombinant enzyme production and characterization, medicinal chemistry, ADME optimization, and the assessment of compounds against hit and lead criteria in well-established in vitro and in vivo models of the primary indication HAT. The investigators will also utilize data sharing practices already established in the community of researchers working on other neglected disease targets, so that the work can contribute to additional efforts against HAT and other illnesses that compromise the overall quality of global health. Human African trypanosomiasis (HAT), also known as Sleeping Sickness, is a serious affliction that affects up to 300,000-500,000 people per year in sub-Saharan Africa, leading to approximately 60,000 deaths annually. A parasitic disease transmitted by the bite of an inflected tsetse fly, HAT is fatal if untreated, yet current drug therapies are not optimal from the perspective of toxicity, dosage regimens, or cost. All of these limitations contribute to lower rates of patient compliance, reducing the likelihood of successful treatments. This project will validate and develop a class of compounds that inhibit two key phosphodiesterase enzymes that have been identified in Trypanosoma sp. and been implicated in parasite viability. Guided by previous results from drug discovery programs that have targeted the human version of these enzymes, we will develop new compounds that target these parasitic enzymes in order to (1) confirm that their inhibition by small molecule drugs leads to parasite death, and (2) produce new drug substances for advancement into clinical studies for this disease.

Public Health Relevance

Human African trypanosomiasis (HAT), also known as Sleeping Sickness, is a serious affliction that affects up to 300,000-500,000 people per year in sub-Saharan Africa, leading to approximately 60,000 deaths annually. A parasitic disease transmitted by the bite of an inflected tsetse fly, HAT is fatal if untreated, yet current drug therapies are not optimal from the perspective of toxicity, dosage regimens, or cost. All of these limitations contribute to lower rates of patient compliance, reducing the liklihood of successful treatments. This project will validate and develop a class of compounds that inhibit two key phosphodiesterase enzymes that have been identified in Trypanosoma sp. and been implicated in parasite viability. Guided by previous results from drug discovery programs that have targeted the human version of these enzymes, we will develop new compounds that target these parasitic enzymes in order to (1) confirm that their inhibition by small molecule drugs leads to parasite death, and (2) produce new drug substances for advancement into clinical studies for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI082577-05
Application #
8240433
Study Section
Special Emphasis Panel (ZAI1-GSM-M (J2))
Program Officer
Rogers, Martin J
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$457,655
Indirect Cost
$106,604
Name
Northeastern University
Department
Chemistry
Type
Schools of Allied Health Profes
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Ochiana, Stefan O; Bland, Nicholas D; Settimo, Luca et al. (2015) Repurposing human PDE4 inhibitors for neglected tropical diseases. Evaluation of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei. Chem Biol Drug Des 85:549-64
Diaz, Rosario; Luengo-Arratta, Sandra A; Seixas, João D et al. (2014) Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign. PLoS Negl Trop Dis 8:e3253
Patel, Gautam; Roncal, Norma E; Lee, Patricia J et al. (2014) Repurposing human Aurora kinase inhibitors as leads for anti-protozoan drug discovery. Medchemcomm 5:655-658
Seixas, João D; Luengo-Arratta, Sandra A; Diaz, Rosario et al. (2014) Establishment of a structure-activity relationship of 1H-imidazo[4,5-c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness. J Med Chem 57:4834-48
Amata, Emanuele; Bland, Nicholas D; Hoyt, Charles T et al. (2014) Repurposing human PDE4 inhibitors for neglected tropical diseases: design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors. Bioorg Med Chem Lett 24:4084-9
Woodring, Jennifer L; Bland, Nicholas D; Ochiana, Stefan O et al. (2013) Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1). Bioorg Med Chem Lett 23:5971-4
Ochiana, Stefan O; Pandarinath, Vidya; Wang, Zhouxi et al. (2013) The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing. Eur J Med Chem 62:777-84
Patel, Gautam; Karver, Caitlin E; Behera, Ranjan et al. (2013) Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis. J Med Chem 56:3820-32
Andriani, Grasiella; Amata, Emanuele; Beatty, Joel et al. (2013) Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. J Med Chem 56:2556-67
Wang, Cuihua; Ashton, Trent D; Gustafson, Alden et al. (2012) Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 1. Sildenafil analogs. Bioorg Med Chem Lett 22:2579-81

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