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Unmet Need
Individuals with impaired immunity, including those with advanced HIV infection, organ transplants, and on immunosuppressive regimens are susceptible to major fungal pathogens, such as Cryptococcus neoformans and Candida albicansCryptococcus neoformans is particularly problematic for AIDS patients.  Over a million people worldwide suffer life-threatening infections with this fungus and as many as 600,000 die each year in Africa alone.  Fluconazole is the most commonly prescribed antifungal medication, but side effects of its use include vomiting, diarrhea, rash, and increased liver enzymes. Serious side effects of the medication include liver problems, seizures, and QT prolongation which can result in sudden death.  Although fluconazole is effective, safer antifungal medications are needed.   
Technology Overview
Fungal cell autophagy is critical for cell survival and has been suggested to be a target for drug development.  Indeed, studies in C. neoformans and C. albicans demonstrated that interference with some components of the autophagy pathway affected cell viability.  Based on this information, Johns Hopkins researchers screened a compound library that targeted autophagosome formation and expansion process in Plasmodium.  They identified a collection of compositions that inhibited or delayed growth of C. neoformans and C. albicans over a period of 72h at 50 μM.  The fact that the compounds targeted both C. neoformans and C. albicans, which are basidiomycetous and ascomycetous yeast, respectively, and thus phylogenetically distant, suggested that these drug candidates are broad antifungal agents. 

Stage of Development
Initial efficacy studies as fungicides have been conducted in C. neoformans and C. albicans showing a minimal inhibition concentration (MIC) of < 7.6 μg/ml, using Fluconazole as a reference.  Ligand-based SAR analysis of compounds 64, 155 or 262 scaffolds predicted >1000, >450 and >2000 diverse analogs of the compounds, respectively, and each are amenable to a multitude of scaffold modifications and functional group decoration.  Three of the compounds are non-toxic in Zebrafish embryo (10 μM) and human foreskin fibroblast (1 μM) and all five compounds have no hERG liability (11 μM). The least toxic compound (Compound 64) shows no toxicity at 32 μM in human fibroblast while being fungicidal at 12 μM and fungistatic at 3 μM. The most potent compound (Compound 262) is fungicidal at 680 nM. The therapeutic indices (TI≥10) are above the threshold required for an in-depth analysis of these candidate topological fungicides.
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
NOVEL ANTI-FUNGAL INHIBITORS PCT: Patent Cooperation Treaty PCT PCT/US2018/065062   12/12/2018     Pending
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Carole Burns
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