# Development of a new class of antifungals effective against Cryptococcus

> **NIH NIH R01** · LINNAEUS BIOSCIENCE, INC. · 2020 · $718,597

## Abstract

Goal: To create a well-tolerated, orally available therapeutic that can be employed alone or in
combination with other antifungal agents to improve treatment outcomes for patients suffering
from cryptococcal meningitis (CM).
 The worldwide disease burden of infections caused by Cryptococcus is over one million cases
annually. The disease is normally caused by inhalation of the fungus, which spreads from the lungs to
the central nervous system in immunocompromised individuals, where it is classified as cryptococcal
meningitis (CM). CM is always fatal if left untreated. First-line therapy is limited to amphotericin B/5-
flucytosine, which is largely unavailable in the developing world.
 Our recent efforts to identify novel therapeutics to treat CM have focused on targeting the fungal
protein Gwt1 acyl transferase, an enzyme that is required for the assembly of
glycosylphosphatidylinositol (GPI) anchored proteins that are later attached to the fungal cell wall.
Amplyx Pharmaceuticals has in-licensed a portfolio of potent Gwt1 inhibitors from Eisai, including
APX001, the first-on-class molecule which has completed Phase 1 clinical trials. APX001A, the active
moiety of APX001, has some activity against Cryptococcus, however, its potency in mouse animal
models is best observed in combination with fluconazole. We have recently synthesized and evaluated
additional Gwt1 inhibitors and have identified several molecules with significantly improved
microbiological activity (> 30-fold) against C. neoformans and C. gattii. In this proposal, Linnaeus
Bioscience Inc. will develop a microscopy based assay for C. neoformans and use it to confirm that the
new molecules target Gwt1, evaluate synergy with other antifungal agents, and explore in vitro and in
vivo phenotypic effects. Dr. John Perfect, Duke University School of Medicine, will evaluate compounds
for efficacy in mouse models of CM. The ultimate outcome of this proposal will be the selection of a
candidate for IND-enabling studies that demonstrates a significant improvement vs APX001 in both CM
survival and fungal burden mouse models.
 We will begin by developing a rapid microscopy assay for determining the mechanism of action
(MOA) of Gwt1 inhibitors in Cryptococcus and apply it to studies of APX001A analogs. We will then
characterize 30 analogs of APX001A molecules that are significantly more potent (4 to >32 fold) than
APX001A vs Cryptococcus. We plan to use our new microscopy based assay to ensure these more
potent molecules are on target. We will also characterize these molecules for their potential cytotoxicity
and metabolic stability. The top 10 compounds will be selected and further studied to characterize their
microbiological activities, including determining their spectrum of activity against a panel of C.
neoformans and C. gattii isolates. We will successfully scale-up the synthesis of 8-10 selected analogs
in prodrug form and assess appropriate formulations for use in animal efficacy studies. ...

## Key facts

- **NIH application ID:** 9870872
- **Project number:** 5R01AI144091-02
- **Recipient organization:** LINNAEUS BIOSCIENCE, INC.
- **Principal Investigator:** Marc Sharp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $718,597
- **Award type:** 5
- **Project period:** 2019-02-12 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870872

## Citation

> US National Institutes of Health, RePORTER application 9870872, Development of a new class of antifungals effective against Cryptococcus (5R01AI144091-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870872. Licensed CC0.

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