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

Author

Listed:
  • Alex J. Callahan

    (Massachusetts Institute of Technology)

  • Satish Gandhesiri

    (Massachusetts Institute of Technology)

  • Tara L. Travaline

    (FOG Pharmaceuticals Inc.)

  • Rahi M. Reja

    (Massachusetts Institute of Technology)

  • Lia Lozano Salazar

    (Massachusetts Institute of Technology)

  • Stephanie Hanna

    (Massachusetts Institute of Technology)

  • Yen-Chun Lee

    (Massachusetts Institute of Technology
    National Cheng Kung University)

  • Kunhua Li

    (FOG Pharmaceuticals Inc.)

  • Olena S. Tokareva

    (FOG Pharmaceuticals Inc.)

  • Jean-Marie Swiecicki

    (FOG Pharmaceuticals Inc.
    Relay Therapeutics, Inc.)

  • Andrei Loas

    (Massachusetts Institute of Technology)

  • Gregory L. Verdine

    (FOG Pharmaceuticals Inc.
    Harvard University
    Harvard University
    Harvard University)

  • John H. McGee

    (FOG Pharmaceuticals Inc.)

  • Bradley L. Pentelute

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard)

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.

Suggested Citation

  • 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 & Gre, 2024. "Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45634-z
    DOI: 10.1038/s41467-024-45634-z
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Shu-Bing Qian & Holly McDonough & Frank Boellmann & Douglas M. Cyr & Cam Patterson, 2006. "CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70," Nature, Nature, vol. 440(7083), pages 551-555, March.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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