Massachusetts Institute of Technology
Abiotic Peptides for the Encoding of Small Molecule Synthesis
Dr. Elizabeth Schram YI Oral Competition
Tuesday, June 27, 2023, at 10:50 am - 11:05 am
Encoded libraries of small molecules have vastly accelerated drug discovery. Most prominently, DNA-encoded libraries have found widespread success and adaption. However, oligonucleotides as carriers of information are hampered by inherent limitations relating to stability, which has limited the synthetic toolbox accessible for small molecule synthesis. Alternative biomolecules may offer transformative potential for encoding technologies, but lack the efficient recording and retrieval of information offered by DNA.
We have established abiotic peptides as a next-generation information storage system suited for the encoding of diverse small molecule synthesis.1 Therein, an encoding alphabet of non-isobaric amino acids in an optimized sequence provided broad chemical stability and high encoding density for sequencing by liquid chromatography-tandem mass spectrometry enabling high-fidelity decoding. Solid- phase combinatorial synthesis facilitated the implementation of peptide-encoded libraries, PELs, wherein the structural information of a small molecule is stored in a covalently linked peptide.
The chemical stability of the peptide-based tag allowed the use of palladium-mediated C–C and C–N bond-forming reactions for the efficient synthesis of PELs with large chemical diversity and excellent purity. Affinity selection against oncogenic proteins afforded an array of small molecules with affinity for the target proteins.
1. Rössler, S. L.; Grob, N. M.; Buchwald, S. L.; Pentelute, B. L. Abiotic Peptides as Carriers of Information for the Encoding of Small-Molecule Library Synthesis. Science, 2023 Mar 3,379(6635),939-945.
Simon Rössler obtained a B.Sc. and M.Sc. in chemistry from the ETH Zürich in Switzerland, during which time he conducted a research fellowship at Harvard University. He then returned to ETH Zürich to join the group of Erick M. Carreira for his Ph.D. focused on synthesis and catalysis. In 2020, he moved back to Boston to join the groups of Stephen L. Buchwald and Bradley L. Pentleute at MIT as an SNSF postdoctoral fellow. His current research is focused on leveraging transition metals for the development of peptide-based modalities, including peptide-encoded libraries of small molecules as a drug discovery platform.