Development of brain-penetrant drugs targeting n. Fowleri primary amoebic meningoencephalitis (PAM)
Active Project Grant Awarded Last action
- Award ID
- R21AI171538
- 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
- $1,083,727
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 85% complete
- Originally
- Place of performance
- La Jolla, CA 92093, USA
Award details come from USAspending.gov.
Description
- Abstract
- The free-living amoeba naegleria fowleri is responsible for severe primary amoebic meningoencephalitis (PAM), which mostly occurs in healthy children and young adults. N. Fowleri is considered as one of the deadliest human pathogens and is a category b biodefence agent. N. Fowleri infection is problematic due to the rapid onset and destructive nature of the disease as well as the lack of effective treatments. Currently, there is no single. Proven. Evidence-based treatment with a high probability of cure. Disruption of sterol biosynthesis in n. Fowleri by smallmolecule inhibitors may be an effective intervention strategy against fatal amoebic meningoencephalitis. In the preliminary studies, we pharmacologically validated n. Fowleri CYP51 (NFCYP51) as a potential therapeutic target. An intrinsic difficulty in achieving anti-naegleria effect in vivo is that a drug must cross the blood-brain barrier (BBB) to reach the site of action. Limited brain permeability of drugs targeting CYP51 in pathogenic fungi prevents them from being efficacious in the treatment of PAM. The goal of our proposal is to develop brainpenetrant bona fide CYP51 inhibitors with anti-naegleria activity and deploy them as the predecessors offuture anti-PAM therapeutics. To achieve this goal, we assembled an interdisciplinary team of investigators with expertise in n. Fowleri biology (debnath, PL), computational chemistry (brancale, CO-i), and medicinal chemistry for CNS applications (ballatore, CO-i). In our preliminary studies, we selected compounds possessing physicochemical parameters compatible with BBB permeability. We identified small-molecule hits that are characterized by the presence of a carboxylate ester moiety which, in vivo, is rapidly hydrolyzed. A follow up study with hydrolytically more stable ether analogs identified two compounds with improved NFCYP51 binding and potency. The in vivo assessment confirmed detection of these two ether analogs in brain tissue. The primary objectives of this application are further evaluation of one BBB permeable ether congener for in vivo efficacy and the design, synthesis, and evaluation of congeners with the carbonyl group isosterically replaced with the 4- membered ring heterocycles, oxetane, thietane or their derivatives, that render compounds more resistant to chemical and enzymatic hydrolysis. Studies in aim 1A include iterative cycles of design and synthesis of the analogs that, based on our current understanding of the structure-activity and structure-property relationships (sarispr), are expected to exhibit both anti-n. Fowleri activity and favorable adme-PK. Studies in aim 1 b will validate the newly synthesized compounds in a cascade of in vitro and in vivo assays for physicochemical properties (PKA, logp, LOG074), aqueous solubility, hydrolytic stability in buffers and plasma, potency, cytotoxicity, BBB permeability, metabolic stability and brain and plasma PK. Two compounds satisfying all go-no-go criteria will progress to tolerability and proof-of-concept efficacy studies in a mouse model of PAM in aim 2. We expect to identify a lead compound that significantly extends the lifespan of the infected animals beyond that of the current standard of care, amphotericin b.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $194,497 | |
| Amendment | $194,497 | |
| Amendment | $23,956 | |
| Amendment | $23,956 | |
| Amendment | $215,607 | |
| Amendment | $215,607 | |
| Original award | $215,607 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Vysoka Skola Chemicko-Technologicka V Praze | $32,270 | |
| Banner Health | $79,769 |
Quick answers
Who received award R21AI171538?
R21AI171538 was awarded to University Of California, San Diego by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on May 23, 2024.
How much is award R21AI171538 worth?
$1,083,727 has been obligated on R21AI171538.
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