A University of Houston professor has received nearly $4 million in new support from the National Institute of Allergy and Infectious Diseases to lead a translational effort turning enzyme-targeting science into urgently needed treatments for Cryptosporidium infections – which are caused by a life-threatening pathogen and have no existing cure.
Cryptosporidium protozoan parasites are among the world's most dangerous waterborne pathogens. Yearly these water-borne parasites (primarily C. hominis and C. parvum) claim the lives of over 50,000 children under five years old, who die of severe diarrhea. They are the second leading cause of diarrhea-related death after rotavirus and can also be fatal for immunocompromised adults.
Also frightening, these parasites have the potential to be deliberately introduced into the water supply, making them a Center for Disease Control Class B bioterrorism agent.
Cryptosporidium stands alone among the top four diarrheal pathogens with no effective treatments or vaccines.
To address this urgent global health challenge, University of Houston's Joseph P. & Shirley Shipman Buckley Endowed Professor of Drug Discovery, Gregory Cuny, will lead a multi-institutional team to develop effective drugs that are urgently needed to manage cryptosporidiosis in young children, immunocompromised adults and as a countermeasure to epidemic outbreaks.
A drug target emerges
An essential enzyme for Cryptosporidium survival – CDPK1 or Calcium dependent protein kinase 1 – has emerged as an attractive target for cryptosporidiosis as scientists find that silencing CDPK1 significantly reduces parasite growth.
Our long-term goal is to identify clinical candidates that can be advanced in our effort to establish CDPK1 as a validated drug target for treatment of Cryptosporidium-induced infections."
Gregory Cuny, University of Houston's Joseph P. & Shirley Shipman Buckley Endowed Professor of Drug Discovery
Cuny and team plan to design the drug candidates to be recyclable to stay in the system longer, absorbed through the liver and then sent to the intestine, instead of being eliminated. It's a process called enterohepatic recycling.
To minimize systemic exposure, they are also designing the drugs to go directly to the gastrointestinal tract, where Cryptosporidium infections primarily occur.
"CDPK1 has structural features that present opportunities for selective inhibitor design targeting the parasite kinase enzyme without harming similar human enzymes," said Cuny. "Demonstrating GI-targeting would also be highly significant to drug design strategies for other GI conditions, such as colonic cancers and inflammatory bowel diseases."
Cuny's team includes Ming Hu, Diana Shu-Lian Chow Endowed Professor of Drug Discovery and Development at UH; Kevin Garey, Robert L. Boblitt Endowed Professor of Drug Discovery at UH; Wesley Van Voorhis, University of Washington; and Saul Tzipori, Tufts University.
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