# Structure-guided development of fungal specific calcineurin inhibitors

> **NIH NIH F31** · DUKE UNIVERSITY · 2021 · $38,402

## Abstract

Abstract
 Systemic fungal infections in immunocompromised patients have exceedingly high mortality rates.
Current antifungal drugs are not sufficient to protect patients from increasing antifungal resistance and a need
for new antifungals is now clearer than ever. However, similarities between targets in these eukaryotic pathogens
and their human hosts have made the development of new antifungal drugs challenging. The natural product
FK506 inhibits the serine-threonine specific protein phosphatase calcineurin in both fungi and humans by binding
to the immunophilin FKBP12 and subsequently binding to calcineurin. In the pathogenic fungi Cryptococcus
neoformans, Candida albicans, and Aspergillus fumigatus, calcineurin is a key virulence factor required for
growth at human body temperature, growth in serum, and the yeast-hyphal dimorphic transition, respectively. In
humans, calcineurin is required for T-cell activation and IL-2 production. In fact, FK506 is used clinically as a
potent immunosuppressant. Although fungal and mammalian calcineurin and FKBP12 are highly conserved, we
have recently identified key amino acid differences in the 80s loop of FKBP12 that are located at the FKBP12-
FK506-calcineurin interface. A recently developed FK506 analog, APX879, is modified at a single moiety of
FK506 (C22 keto oxygen) that approaches the FKBP12 80s loop. This analog exhibits significantly reduced
immunosuppressive activity yet retains antifungal activity in vitro and in an animal model of cryptococcosis. Our
central hypothesis is that with structure-guided rational design, FK506 analog calcineurin inhibitors can be
generated with increased fungal specificity by introducing differential interactions in the 80s loop of FKBP12. In
Aim 1, a defined library of FK506 analogs will be designed and synthesized based on the predicted interactions
with known crystal structures for the calcineurin ternary complexes from fungi and mammals. The structure-
activity relationship will then be determined by testing the spectrum of antifungal activity and the
immunosuppressive activity of this library. In Aim 2 lead compounds will be tested for in vivo efficacy in murine
models of cryptococcosis and in vivo immunosuppression. By defining the small molecule interactions between
calcineurin, FKBP12, and FK506, compounds will be developed that shift the efficacy of calcineurin inhibition in
vivo into the therapeutic window of higher antifungal activity and reduced immunosuppressive activity.

## Key facts

- **NIH application ID:** 10231079
- **Project number:** 5F31AI150120-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Michael Hoy
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,402
- **Award type:** 5
- **Project period:** 2020-08-01 → 2022-06-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231079

## Citation

> US National Institutes of Health, RePORTER application 10231079, Structure-guided development of fungal specific calcineurin inhibitors (5F31AI150120-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231079. Licensed CC0.

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