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Peer-reviewedCC BY-NC 3.0Chemical Science

On-resin Heck coupling enables small-molecule ligand discovery with covalent peptide-encoded libraries

  • Ching-Pei Hsu1
  • Michael Desgagné1
  • Simon L. Rössler1
  • Nathalie M. Grob1
  • Charlotte E. Farquhar1
  • Andrei Loas1
  • Zena D. Jensvold2
  • Hannah T. Baddock2
  • Matthew Bratkowski2
  • Aaron H. Nile2
  • Bradley L. Pentelute1,3,4
4 affiliations
  1. 1Department of Chemistry, Massachusetts Institute of Technology Cambridge MA 02139 USA
  2. 2Calico Life Sciences LLC South San Francisco CA 94080 USA
  3. 3The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology Cambridge MA 02139 USA
  4. 4Center for Environmental Health Sciences, Massachusetts Institute of Technology Cambridge MA 02139 USA
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Abstract

Heck coupling remains challenging in solid-phase peptide synthesis (SPPS) and diversification of combinatorial small-molecule libraries. The intermolecular Heck reaction has not yet been implemented in SPPS, owing to the lack of effective catalysts achieving broad substrate scopes on resin-bound peptides. Peptide-encoded libraries (PELs) enable high-throughput identification of small-molecule ligands to protein targets and allow access to structurally diverse chemotypes. Here, we introduce a covalent PEL (coPEL) platform that incorporates on-resin Heck coupling to derivatize cysteine-reactive scaffolds during solid-phase library synthesis. We leverage the specific reactivity of palladium catalysts derived from tBuDavePhos to enable intermolecular on-resin Heck coupling reactions to rapidly diversify covalent acrylamide warheads. The optimized reaction conditions are high-yielding across a broad range of (hetero)aryl halides and acrylamides, ensuring robust performance and versatility within the coPEL platform. Screening a model coPEL against the epidermal growth factor receptor (EGFR) tyrosine kinase yielded original low-micromolar covalent inhibitors. This work establishes intermolecular on-resin Heck coupling as a practical tool for SPPS and expands the accessible chemical space for covalent ligand discovery.

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Cite

BibTeXRIS
BibTeX
@article{hsu2026onresin,
  title = {{On-resin Heck coupling enables small-molecule ligand discovery with covalent peptide-encoded libraries}},
  author = {Ching-Pei Hsu and Michael Desgagné and Simon L. Rössler and Nathalie M. Grob and Charlotte E. Farquhar and Andrei Loas and Zena D. Jensvold and Hannah T. Baddock and Matthew Bratkowski and Aaron H. Nile and Bradley L. Pentelute},
  journal = {Chemical Science},
  year = {2026},
  month = aug,
  doi = {10.1039/d6sc05323h},
  url = {https://doi.org/10.1039/d6sc05323h},
  note = {CC BY-NC 3.0},
}
RIS
TY  - JOUR
TI  - On-resin Heck coupling enables small-molecule ligand discovery with covalent peptide-encoded libraries
AU  - Ching-Pei Hsu
AU  - Michael Desgagné
AU  - Simon L. Rössler
AU  - Nathalie M. Grob
AU  - Charlotte E. Farquhar
AU  - Andrei Loas
AU  - Zena D. Jensvold
AU  - Hannah T. Baddock
AU  - Matthew Bratkowski
AU  - Aaron H. Nile
AU  - Bradley L. Pentelute
PY  - 2026
DA  - 2026/08/25
JO  - Chemical Science
DO  - 10.1039/d6sc05323h
UR  - https://doi.org/10.1039/d6sc05323h
AB  - Heck coupling remains challenging in solid-phase peptide synthesis (SPPS) and diversification of combinatorial small-molecule libraries. The intermolecular Heck reaction has not yet been implemented in SPPS, owing to the lack of effective catalysts achieving broad substrate scopes on resin-bound peptides. Peptide-encoded libraries (PELs) enable high-throughput identification of small-molecule ligands to protein targets and allow access to structurally diverse chemotypes. Here, we introduce a covalent PEL (coPEL) platform that incorporates on-resin Heck coupling to derivatize cysteine-reactive scaffolds during solid-phase library synthesis. We leverage the specific reactivity of palladium catalysts derived from tBuDavePhos to enable intermolecular on-resin Heck coupling reactions to rapidly diversify covalent acrylamide warheads. The optimized reaction conditions are high-yielding across a broad range of (hetero)aryl halides and acrylamides, ensuring robust performance and versatility within the coPEL platform. Screening a model coPEL against the epidermal growth factor receptor (EGFR) tyrosine kinase yielded original low-micromolar covalent inhibitors. This work establishes intermolecular on-resin Heck coupling as a practical tool for SPPS and expands the accessible chemical space for covalent ligand discovery.
SN  - 2041-6520
SN  - 2041-6539
ER  -