# Chemoproteomic mapping of the ligandable ribonucleoproteome using phloroglucinol meroterpenoids

> **NIH NIH R35** · CORNELL UNIVERSITY · 2022 · $386,013

## Abstract

The long-term goal of the PI’s research program is to understand how RNAs exert their regulatory effects through
interaction with RNA-binding proteins (RBPs) and identify the basis for their therapeutic effects in human diseases.
RBPs interact with RNAs to form ribonucleoprotein complexes that that control the fate of nearly every transcript.
These roles are essential for normal human physiology, as defects in RBP function are implicated in autoimmunity,
neurodegeneration, cancer, and innate antiviral immune response.
The molecular mechanisms of RNA-protein
interactions (RPIs) that underpin gene expression and form the basis of numerous human diseases remain
obscure. Consequently, RBPs are rapidly emerging as promising targets for the development of chemical probes
and candidate therapeutic agents. The discovery of therapeutically tractable RPIs, however, remains a formidable
challenge. This proposal describes an interdisciplinary program leveraging quantitative chemoproteomics, natural
product synthesis, molecular biology, and biochemistry to exploit reactivity of proteinaceous lysines at the RPI
interface that modulate the structural properties of ribonucleoprotein complexes. Preliminary findings from the PI
demonstrate that phloroglucinol meroterpenoid natural products modulate RPIs through reversible-covalent
modification of RNA-binding lysines in RBPs. The central hypothesis of this proposal is that high occurrence of
reactive lysines at the RPI interface may provide an unprecedented opportunity in the development of precision
chemical tools with specificity for RBPs and on-target potency gained through reversible-covalent modification.
 The proposed research program embodies three integrated projects that address specific challenges in
targeting RBPs in human cells. First, the lack of traditional enzymatic pockets or functional epitopes renders RBPs
as canonically intractable targets. This proposal aims to overcome this challenge through reversible-covalent
modification of RNA-binding lysines at the RPI interface using phloroglucinol meroterpenoids. Second, the full
complement of lysines with heightened reactivity at the RPI interface remains unexplored. This proposal aims to
overcome this limitation by using innovative chemoproteomic methods to globally map lysine reactivity and
ligandability directly in human cells. Last, the functional consequences of meroterpenoid-lysine interactions remain
obscure. By leveraging integrative RNA pulldown and extraction methods with RNA-interactome capture and
immunofluorescence imaging, the proposal aims to identify advanced tool compounds that perturb RPIs through
site-selective modification of lysines in RBPs. Overall, the proposed research program is significant because over
the next five years it will deliver innovative chemical tools and proteomic methods that enrich understanding of the
pathophysiological functions of RPIs and identify the basis for their therapeutic effects in human diseases.
Thi...

## Key facts

- **NIH application ID:** 10434114
- **Project number:** 5R35GM143027-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Mikail E Abbasov
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $386,013
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434114

## Citation

> US National Institutes of Health, RePORTER application 10434114, Chemoproteomic mapping of the ligandable ribonucleoproteome using phloroglucinol meroterpenoids (5R35GM143027-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10434114. Licensed CC0.

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