# Peptide-Conjugated Palladium Oxidative Addition Complexes for Site-Selective Arylation Chemistry

> **NIH NIH F32** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $74,284

## Abstract

PROJECT SUMMARY/ABSTRACT
 The site-selective chemical modification of biomolecules including proteins and biologically active small
molecules is currently recognized as an important and unmet challenge in chemical biology. While current
strategies for chemical protein modification have proven highly enabling for a variety of applications related to
mechanistic biology and the production of biomaterials and pharmaceuticals, site-selective approaches are rare
and highly valued. The first Aim of this proposal details a strategy to access well-defined site-selectively labeled
protein conjugates for varied applications across chemical biology. Central to the thesis of this proposal is the
use of palladium oxidative addition complexes that have been previously shown by the Buchwald and Pentelute
labs to efficiently engage protein targets in C–heteroatom arylation reactions under mild physiological conditions.
The covalent derivatization of these palladium-based reagents with peptide sequences that bind a protein of
interest is proposed as a strategy to achieve site-selective protein cysteine arylation in both intra- and
intermolecular contexts. These technologies are expected to enable a myriad of applications including the
formation of site-selectively modified antibody-drug-conjugates and selective protein degrading platforms. In an
effort to significantly simplify drug structure-activity-relationship studies and produce valuable probes for
mechanistic biology, the second Aim of this proposal extends peptide-conjugated palladium arylation chemistry
to the regioselective modification of biologically-active small molecules. While current approaches to site-
selective small molecule derivatization generally operate on a narrow range of substrate classes and lack
generality, this proposal aims to deliver a general and highly modular approach to site-selective arylation of
complex polyol and polyamine targets, reliant on the well-defined secondary structure that peptide conjugates
impart about the Pd active site. Overall, the proposed the site-selective bioconjugation approach detailed in this
proposal will have the potential to be highly impactful for chemical biology by enabling powerful discovery
platforms for mechanistic biology and pharmaceutical applications. The objectives of this proposal are directly
related to the advancement of human health, are well aligned with the aims of the NIH.
 With the ultimate goal of securing an academic position at a major research university, the Buchwald
and Pentelute laboratories at the Massachusetts Institute of Technology represent an ideal setting in which to
conduct my postdoctoral training in organometallic bioconjugation. The Buchwald lab’s expertise in metal-
catalyzed cross-coupling and its application to C–heteroatom bond forming processes and the Pentelute lab’s
focus within chemical biology and peptide synthesis will be instrumental in the execution of the proposed
research. During my training, I will g...

## Key facts

- **NIH application ID:** 10912476
- **Project number:** 5F32GM150211-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Dennis A. Kutateladze
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912476

## Citation

> US National Institutes of Health, RePORTER application 10912476, Peptide-Conjugated Palladium Oxidative Addition Complexes for Site-Selective Arylation Chemistry (5F32GM150211-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10912476. Licensed CC0.

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