Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins

Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins

Alex J. Callahan, Satish Gandhesiri, Tara L. Travaline, Rahi M. Reja, Lia Lozano Salazar, Stephanie Hanna, Yen-Chun Lee, Kunhua Li, Olena S. Tokareva, Jean-Marie Swiecicki, Andrei Loas, Gregory L. Verdine, John H. McGee & Bradley L. Pentelute
Nature Communications

Abstract

Widespread adoption of mirror-image biological systems presents difficulties in accessing the requisite D-protein substrates. In particular, mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders with potentially unique recognition modes but is hindered by the individualized optimization required for D-protein chemical synthesis. We demonstrate a general mirror-image phage display pipeline that utilizes automated flow peptide synthesis to prepare D-proteins in a single run. With this approach, we prepare and characterize 12 D-proteins – almost one third of all reported D-proteins to date. With access to mirror-image protein targets, we describe the successful discovery of six macrocyclic D-peptide binders: three to the oncoprotein MDM2, and three to the E3 ubiquitin ligase CHIP. Reliable production of mirror-image proteins can unlock the full potential of D-peptide drug discovery and streamline the study of mirror-image biology more broadly.

Category
2024, Publications