Neglected tropical diseases (NTD) include 13 poverty-promoting parasitic and bacterial infections that affect over 1 billion people worldwide, primarily in impoverished regions. One NTD for which there is a great need for a therapeutic evolution is onchocerciasis, or river blindness, a leading cause of blindness in the developing world. The infection is caused by the parasitic nematode Onchocerca volvulus, which is transmitted to humans by the blackfly. Despite several eradication efforts, the disease affects more than 37 million people in Africa, Central and South America and Yemen. Currently, the only drug available for mass treatment is ivermectin (Mectizan(R), Merck). Although this drug has proved successful in reducing morbidity, resistance to ivermectin is emerging. Despite the gravity of such diseases on human health, the pharmaceutical industry has largely neglected the development of chemotherapies for NTDs and no new anthelmintic classes for humans have been described within the past 15 years. Thus, there is a crucial need to identify chemical probes toward the goal of validating new therapeutic targets for the development of effective treatments for onchocerciasis. Recently, our laboratory has investigated the O. volvulus chitinase, OvCHT1, as an antilarval drug target. As a starting point, we screening The Johns Hopkins Clinical Compound Library and uncovered the known veterinary anthelmintic drug, closantel, as a chitinase inhibitor. Using function-specific chemical probes based upon closantel's general scaffolding, we have explored both small molecule OvCHT1 inhibitors and proton ionophores as anti-molting agents, as closantel possesses both of these biochemical activities. Interestingly, initial studies indicate that both activities are required for potent inibition of molting;however, further studies are required to unravel how each mechanism of action impacts larval development. To gain a deeper understanding, we will adopt both chemical- and biological-mediated modulation tactics by using small molecule chemical probes and RNAi. From these studies we hope to not only be able to address the druggability of filarial chitinases but also provide useful insights toward the goal of validating chitinases as a new therapeutic target for the development of effective treatments for onchocerciasis.

Public Health Relevance

Onchocerciasis, or river blindness, is a parasitic neglected tropical disease that affects more than 37 million people in Africa, Central and South America and Yemen. Despite the gravity of this and other parasitic diseases with respect to human health, no new therapeutic targets have been explored for these diseases;however, recently, an enzyme (a chitinase) has been implicated in development of the parasite responsible for onchocerciasis. Using both chemical and biological tactics, we hope to explore the importance of this chitinase and its impact on parasite development in onchocerciasis with an ultimate goal of validating this enzyme as a therapeutic target for filarial parasitic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI092076-02
Application #
8606389
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Rogers, Martin J
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$213,188
Indirect Cost
$100,688
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Gooyit, Major; Tricoche, Nancy; Lustigman, Sara et al. (2014) Dual protonophore-chitinase inhibitors dramatically affect O. volvulus molting. J Med Chem 57:5792-9