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

doi:10.1038/s41467-024-45634-z

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

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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.

Original language	English
Article number	1813
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-45634-z
Publication status	Published - 2024 Dec

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Callahan, A. J., Gandhesiri, S., Travaline, T. L., Reja, R. M., Lozano Salazar, L., Hanna, S., Lee, Y. C., Li, K., Tokareva, O. S., Swiecicki, J. M., Loas, A., Verdine, G. L., McGee, J. H., & Pentelute, B. L. (2024). Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins. Nature communications, 15(1), Article 1813. https://doi.org/10.1038/s41467-024-45634-z

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title = "Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins",

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.",

author = "Callahan, {Alex J.} and Satish Gandhesiri and Travaline, {Tara L.} and Reja, {Rahi M.} and {Lozano Salazar}, Lia and Stephanie Hanna and Lee, {Yen Chun} and Kunhua Li and Tokareva, {Olena S.} and Swiecicki, {Jean Marie} and Andrei Loas and Verdine, {Gregory L.} and McGee, {John H.} and Pentelute, {Bradley L.}",

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doi = "10.1038/s41467-024-45634-z",

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AU - Lozano Salazar, Lia

AU - Hanna, Stephanie

AU - Lee, Yen Chun

AU - Li, Kunhua

AU - Tokareva, Olena S.

AU - Swiecicki, Jean Marie

AU - Loas, Andrei

AU - Verdine, Gregory L.

AU - McGee, John H.

AU - Pentelute, Bradley L.

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

Abstract

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