# Targeting the large cyclophilins through an autonomous CONA assay

> **NIH NIH R21** · XENOBE RESEARCH INSTITUTE · 2022 · $422,950

## Abstract

Project Summary. Cyclophilins and FKBPs are members of a large class of Peptidyl-Proline Isomerases
(PPIases) and play a central role in modern medicine with clinical applications in immunosuppression,
infectious disease, and chemotherapy. Although decades of effort have revealed the remarkable structural
features of immunophilin enzymes, many members of this family, including Cyp40, have yet to meet the critical
level of therapeutic examination. Recently our team described a system that uses beads to rapidly enhance the
discovery of probes that target specific domains within a protein. In this program our team develops this
method, as a technique to discover molecular probes to study the neurological roles of the immunophilins. The
extracellular amyloid plaques and the intracellular neurofibrillary tangles (tau) that define the neuropathology of
Alzheimer's disease are both regulated by the large immunophilins. Cyclophilin 40 (Cyp40), FK506-binding
proteins FKBP51 and FKBP52 play important, but antagonistic roles. Cyp40 disaggregates α-synuclein and
overexpression rescues tau-induced cognitive deficits and unravels neurotoxic plaques. Both Cyp40 and
FKBP51 promote the stabilisation of microtubules while FKBP52 has been shown to cause memory
impairments in a tau transgenic mouse model and to promote tau pathogenesis. A likely mechanism involves
the opposing roles played by Cyp40 and FKPB52 in regulating microtubule depolymerisation. FKBP52 has
been shown to bind and inhibit tubulin formation via direct binding by its TPR domain. As the amino acid
identity between these three large immunophilin TPR domains is less than 26%, it will be possible to identify
small molecule binders that distinguish between the TPR domains of Cyp40, FKBP51 and FKBP52.
Modulating the effects of the large immunophilins will provide a new form of therapy to treat neurodegenerative
diseases caused by plaque formation including Alzheimer's disease. Here, our team adapts an optimized
workflow that uses beads, called Confocal Nanoscanning (CONA) as a tool to identify and validate fluorescent
natural products that bind with high or medium affinity to Cyp40, FKBP51 or FKBP52. The resulting materials
are then used to establish methods for cellular imaging as well as establish a high-throughput screen for each
of these large immunophilins.

## Key facts

- **NIH application ID:** 10509443
- **Project number:** 1R21NS128597-01
- **Recipient organization:** XENOBE RESEARCH INSTITUTE
- **Principal Investigator:** James J La Clair
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $422,950
- **Award type:** 1
- **Project period:** 2022-09-02 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10509443

## Citation

> US National Institutes of Health, RePORTER application 10509443, Targeting the large cyclophilins through an autonomous CONA assay (1R21NS128597-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10509443. Licensed CC0.

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