Repurposing the CNS-penetrant small molecule Q134R as a novel therapeutic for cryptococcal infection

Active Project Grant Awarded Last action

Award ID
F32AI203016
Recipient
Awarding agency
Obligated
$76,300

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 0% complete
Place of performance
Gainesville, FL 32611, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Cryptococcus neoformans (CN) is an encapsulated and neurotropic fungus that causes cryptococcal meningoencephalitis (CME), particularly in immunocompromised individuals. CME results in high mortality rates (20-70%) even with optimal antifungal treatment. The rising number of immunocompromised individuals prompted the world health organization to place CN at the top of its priority list of fungal pathogens. Although amphotericin B and 5-fluorocytosine are the gold standard for CME treatment, their use is limited by significant toxicities. Access and cost further restrict their use in resource-limited regions, especially in sub-saharan africa. As a result, oral fluconazole, a widely available azole, is often used during maintenance phase following the standard treatment. However, fluconazole is suboptimal as a monotherapy due to its poor fungicidal activity, leading to frequent treatment failure and relapse. This highlights the urgent need to develop novel anti- cryptococcal treatments. Here, we screened a central nervous system (CNS)-penetrant library of 919 FDA- approved drugs and clinical compounds and identified Q134R as potent inhibitor of CN. Our objective is to develop an efficacious anti-cryptococcal CNS-penetrant molecule to combat brain infection in a CD4 T-cell depleted mouse model, which mimics HIV/aids immunosuppression and CME pathology. We will test the central hypotheses that Q134R will have anti-cryptococcal activity, combat CME, and minimize CME sequelae in the setting of immunosuppression. Additionally, we seek to elucidate the mechanism by which Q134R exerts its anti- cryptococcal activity. Furthermore, Q134R's CNS bioavailability and safety profile make IT an attractive candidate for repurposing to combat CME.

Quick answers

Who received award F32AI203016?

F32AI203016 was awarded to University Of Florida by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 10, 2027.

How much is award F32AI203016 worth?

$76,300 has been obligated on F32AI203016.

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