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Therapeutic Agents Targeting Cryptococcal Infections

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI172564-01A1
Agency Tracking Number: R41AI172564
Amount: $300,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA22-178
Timeline
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-03-08
Award End Date (Contract End Date): 2025-02-28
Small Business Information
400 Farmington Avenue
Farmington, CT 06032-3449
United States
DUNS: 080447260
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 DENNIS WRIGHT
 (860) 486-9451
 dennis.wright@uconn.edu
Business Contact
 ADRIAN MOSLEY
Phone: (925) 457-9906
Email: amosley@quercusmoleculardesign.com
Research Institution
 UNIVERSITY OF CONNECTICUT
 
Sponsored Program Services 438 Whitney Road Extension, Unit 1006
STORRS, CT 06269-1006
United States

 Nonprofit College or University
Abstract

Cryptococcus species are a clinically important group of opportunistic fungal pathogens that can cause life
threatening disease, particularly in the immunocompromised patient population. Historically, this has involved
patients with advanced HIV, but is becoming more prevalent in other immunovulnerable populations. The primary
pathogens, C. neoformans and C. gattii, are ubiquitous in the environment which provides ample opportunity to
establish primary pulmonary infections upon inhalation of the corresponding spore or yeast. Unfortunately, many
cases of pulmonary cryptococcosis can progress and lead to deadly disseminated fungal infections. Of special
importance is the strong preference (~90%) for the pathogen to establish infection within the central nervous
system, especially through infection of the meninges leading to cryptococcal meningitis. This is the leading cause
of meningitis world-wide and is associated with a very high mortality rate (~80%). Treatment of cryptococcal
infections is difficult owing to the limited number of effective treatment options available. The difficulty of many
antifungal drugs to effectively traverse the blood-brain barrier and reach therapeutically relevant concentration
within the CNS limits current treatment options to just three agents: fluconazole, 5-flucytosine and amphotericin.
The evolution of substantial levels of resistance to fluconazole and 5-flucytosine in circulating strains of
Cryptococcus has significantly undermined these agents while the toxicities associates with amphotericin are a
well-known problem. Based on the limited options for treating these life-threatening infections, there is a
compelling need to develop more effective agents capable of reaching the CNS. QMD is developing antifungal
antifolates that inhibit the essential enzyme dihydrofolate reductase (DHFR). Although DHFR is a clinically
validated target in several eukaryotic pathogens such as Plasmodium falciparum and Toxoplasma gondii, the
efforts to exploit this target for antifungal drug development has lagged far behind. QMD has identified a novel
inhibitor against Cryptococcus that is characterized by high levels of antifungal activity while initial dose-tolerance
and pharmacokinetic studies suggest the compound has a favorable profile to demonstrate in vivo efficacy in
animal models of infection. In this Phase I application, we will work to advance this program for the treatment of
cryptococcal infections by (1) antimicrobial profiling, PK/PD studies and elucidation of mechanism(s) of
resistance, (2) exploring structural modifications to increase the selectivity index over the host enzyme, and (3)
evaluation of lead and back-up compounds in murine models of infection. Successful demonstration in proof-of-
concept in vivo efficacy will enable us to further advance these antifungal candidates toward clinical application.

* Information listed above is at the time of submission. *

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