# The catalytic core of the proteasome as a drug target to treat Human African Trypanosomiasis

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $197,500

## Abstract

PROJECT SUMMARY
Human African Trypanosomiases (HAT) is a disease of poverty caused by various sub-species of the
Trypanosoma brucei protozoan parasite. Transmitted by the bite of the tse-tse fly, Stage 1 disease is
characterized by trypanosomes that disseminate through the blood and lymphatic systems, and then cross the
blood-brain barrier into the CNS to cause Stage 2 disease. Infiltration of the CNS is associated with a frightening
array of progressively deteriorating and eventually lethal psychological and physiological disorders. Drug
therapy relies on antiquated and often toxic drugs that must be administered under medical supervision and for
which resistance is established or a constant threat. New drugs are needed. The proteasome is an evolutionarily-
conserved, multi-subunit protein complex in the cell that regulates normal protein turnover and degradation of
misfolded proteins. Inhibition of the T. brucei proteasome (Tb20S) with small molecule inhibitors kills
trypanosomes. However, there is little information regarding the proteolytic cleavage preferences or the
inhibition profile of the Tb20S target. Uncovering this information would support the development of
proteasome inhibitors with improved specificity and potency that could then form the basis for a new treatment
of HAT. Accordingly, in Aim 1 we will comprehensively profile the cleavage specificity of Tb20S using a
technology called multiplex substrate profiling by mass spectrometry (MSP-MS). The data arising will inform (i)
the synthesis of optimized peptidyl substrates with which the activity of Tb20S can be measured and (ii) a
medicinal chemistry effort (Aim 3) to synthesize new Tb20S inhibitors with improved specificity. In Aim 2, we
will screen Tb20S with various proteasome inhibitor libraries containing diverse scaffolds and reactive groups
that have been developed in-house and by collaborators. The data arising will inform (i) the broader chemical
space associated with inhibition of Tb20S and (ii), again, the medicinal chemistry program planned for Aim 3.
For Aim 3, we will screen both Trypanosoma brucei and mammalian cell lines with the top performing Tb20S
inhibitors to understand the differential between parasite-killing and cytotoxicity. This Aim also involves a
focused medicinal chemistry campaign that evaluates all of the proteasome inhibition and cell screening data to
synthesize Tb20S inhibitors with improved specificity using the scaffold of the marine natural product known as
carmaphycin B. Upon completion of the proposed R21 studies, we will have identified a series of Tb20S
inhibitors ready for further development as therapeutics for HAT.

## Key facts

- **NIH application ID:** 10677879
- **Project number:** 5R21AI171824-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Conor Caffrey
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $197,500
- **Award type:** 5
- **Project period:** 2022-08-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10677879

## Citation

> US National Institutes of Health, RePORTER application 10677879, The catalytic core of the proteasome as a drug target to treat Human African Trypanosomiasis (5R21AI171824-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10677879. Licensed CC0.

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