Proteasome inhibitors as a novel drug-class for treatment of giardiasis
Active Project Grant Awarded Last action
- Award ID
- F31AI186328
- Recipient
-
University Of California, San Diego UEI UYTTZT6G9DT1
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $87,252
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Originally
- Place of performance
- California, USA
Award details come from USAspending.gov.
Description
- Abstract
- Giardia lamblia (G. Lamblia) is a protozoan pathogen that colonizes the mucosa of the intestinal tract and causes diarrheal disease and malnutrition with hundreds of millions of annual cases worldwide. In the united states, G. Lamblia is one of the two most common causes of outbreaks of parasitic disease, with prevalence rates of 1-7%, particularly among children in day-care centers, travelers, hikers, and military personnel. Symptomatic infection is characterized by diarrhea, epigastric pain, nausea, vomiting, malabsorption and malnutrition, and protracted post-infectious syndromes. Treatment of giardiasis is primarily with oral nitro- heterocyclic drugs, but they can have significant adverse effects and treatment failures and resistance occurs in a significant fraction of patients. A better understanding of the basic cell biology and exploration of new drug targets in G. Lamblia is critical for developing new treatment and prevention strategies. The proteasome is an essential large multi-subunit protease complex found in all eukaryotes and subsets of prokaryotes. IT regulates numerous cellular functions, including general protein turnover for recycling of amino acids, selective degradation of specific proteins involved in cell signaling, and degradation of misfolded proteins. In preliminary studies in the O'donoghue lab, we discovered that G. Lamblia is sensitive to an FDA-approved proteasome inhibitor, carfilzomib. While this anti-cancer drug validates the giardia proteasome as a druggable target, IT's toxicity profile would prevent IT from being used to treat giardia infections. The O'donoghue lab has previously developed proteasome inhibitors that are >2,600-fold more potent at killing parasites (such as plasmodium falciparum) than human cells. This project aims to recombinantly express and isolate the G. Lamblia proteasome and further investigate its substrate cleavage preferences relative to the human proteasome using multiplex substrate profiling by mass spectrometry (MSP-MS). Collaborating with william gerwick at scripps institute of oceanography, we will design ~30 inhibitors that are expected to be selective for the parasite proteasome over the human proteasome. Evaluation in cellular and biochemical assays will further guide the structural modification and optimization of these inhibitors. Although outside of the project scope, the ultimate objective is to develop an oral proteasome inhibitor for treating giardia infections. Additionally, the project involves CRYO-electron microscopy (CRYO-EM) to unveil the 3D structure of the recombinant G. Lamblia proteasome. CRYO-EM will also be employed to explore the structure-activity relationship of newly developed inhibitors and probes. This proposed project holds significance in unraveling the role of the G. Lamblia proteasome in basic giardia biology, as well as its value as a target in drug discovery and design and treatment of giardiasis. IT will yield molecular tools, such as novel reporter substrates and rationally designed inhibitors, and potentially a new class of anti-giardial therapeutics.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $43,626 | |
| Amendment | $0 | |
| Original award | $43,626 |
Quick answers
Who received award F31AI186328?
F31AI186328 was awarded to University Of California, San Diego by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on November 27, 2026.
How much is award F31AI186328 worth?
$87,252 has been obligated on F31AI186328.
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