# Development of a novel broad spectrum antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis

> **NIH NIH R42** · PROKARYOTICS, INC. · 2024 · $295,592

## Abstract

Widespread azole resistance among Candida and Aspergillus spp. along with emerging echinocandin
resistance in C. glabrata and C. auris raises the specter of untreatable multidrug resistant fungal infections,
even as advances in medicine (cancer chemotherapy, organ transplant, premature infants, HIV/AIDS therapy)
have increased the size of the vulnerable population. Our proposal aims to develop a novel broad spectrum
antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis to treat life threatening
infections due to drug resistant Candida and Aspergillus with no cross resistance to existing agents. Our
Aims are:
Aim 1 (Phase 1). Demonstrate improved efficacy is achievable by optimizing pharmacokinetic (PK)
properties of the series. Perform metabolic identification (MetID) studies on M743, M720, and the hydrolyzed
core lacking the sidechain to identify oxidative metabolic hotspots to guide a limited Lead Optimization (Lead
Opt) effort to improve PK properties of the series while maintaining potency, spectrum, target selectivity, and
minimizing cytotoxicity. Test up to 2 new analogs in a murine systemic infection model of Candidiasis with and
without 1-aminobenzotriazole (ABT) PK enhancer codosing. Milestone 1. Based on MetID studies, synthesize
up to 30 new M743 analogs. An analog showing an IP-administered dose-dependent > 3 log10 reduction in
fungal burden in a murine Candidiasis model (i.e. superior to M720 efficacy) with or without ABT codosing will
identify the key (and addressable) liability of the series and warrant advancement of the program to Ph 2.
Aim 2 (Phase 2). M743 scale up, Lead Opt and in vitro characterization of compounds. Produce M743
on scale sufficient to supply a full Lead Opt effort based on MetID data and emerging SAR. Characterize
analogs as in Aim 1 with additional emphasis on PK, MOA, reduced serum binding, and cytotoxicity. Milestone
2. Obtain 3g of M743; semisynthesize up to 100 new analogs. Identify up to 3 analogs with acceptable potency
and PK (without ABT codosing), along with validated target engagement, FOR <1 x 109, in vitro synergy with
Gwt1 inhibitor, APX001A (FICI<0.5), progressible activity in serum, and acceptable toxicity (in vivo cytotoxicity
vs. HepG2, in vitro IC50>10 uM vs ion channels, CYPs, critical PANLABS targets) to advance to Aim 3.
Aim 3 (Phase 2). In vivo Characterization. Efficacy of up to 2 compounds will be tested in a murine
Candidiasis (including codosing with APX001 to evaluate in vivo synergy) and Invasive Pulmonary
Aspergillosis infection models without ABT codosing. Milestone 3. Semisynthesize 200 mg of each test
compound. Demonstrate acceptable MIC90 across Candida/Aspergillus spp. Identify suitable formulation for IP
dosing. Conduct dose-ranging studies to gauge exposures and tolerability at higher doses to guide dose
selection. Top analog achieving dose-dependent efficacy in each infection model (> 3 log reduction in burden
over therapeutic duration) and over...

## Key facts

- **NIH application ID:** 10907819
- **Project number:** 5R42AI179344-02
- **Recipient organization:** PROKARYOTICS, INC.
- **Principal Investigator:** Terry Roemer
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $295,592
- **Award type:** 5
- **Project period:** 2023-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907819

## Citation

> US National Institutes of Health, RePORTER application 10907819, Development of a novel broad spectrum antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis (5R42AI179344-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10907819. Licensed CC0.

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