# Sequence Specific Inhibition of Protein Translation

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $201,875

## Abstract

PROJECT SUMMARY/ABSTRACT
An inherent challenge in drug discovery is that every target requires its own individualized strategy. Many
targets are “undruggable” by small molecules, which, owing to their rapid onset and low cost, are the
pharmacologic cornerstone of both clinical therapies and research tools alike. A generalizable solution to inhibit
the function of any given protein with a small molecule is therefore a holy grail of biomedical research. A
possible solution exists in a recently described small molecule which stalls the translation of a very limited
number of protein targets. This class of molecules binds in the ribosome exit tunnel to allosterically alter the
peptidyl transferase center and prevent elongation, doing so in a manner that is dependent on the sequence
identity of nascent chain. Though this novel mechanism of action is exciting, the off-target effects of the current
compounds precludes their use either as therapeutics or as a clean sequence-specific chemical probe. In this
proposal, we will directly address whether these compounds can be developed into useful research tools. In
Aim 1, we will probe the intrinsic limits of the specificity of this technology, doing so by developing an optimized
chemical genetics pair between the known compounds and an evolved target peptide sequence. In Aim 2, we
will evaluate whether the maximum efficacy of these compounds can be improved by developing covalent
analogs that can target specific cysteine-containing nascent chains. In Aim 3, we will ask whether the
structures of the compounds can be tuned to alter the sequence specificity of the nascent chains they target.
We will do this via an innovative kinetic target-templated synthetic strategy, which will simultaneously probe the
accessible chemical space of the binding pocket with the exit tunnel, while also producing nascent chain
specific chemical probes. We anticipate that advances in any one of these Aims would allow this technology to
be further developed into a powerful tool: the ability to stop, and then restart, the protein production of any
target of interest.

## Key facts

- **NIH application ID:** 10379318
- **Project number:** 5R21GM141609-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John S Chorba
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $201,875
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379318

## Citation

> US National Institutes of Health, RePORTER application 10379318, Sequence Specific Inhibition of Protein Translation (5R21GM141609-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379318. Licensed CC0.

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