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Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale

Author

Listed:
  • Sevan Habeshian

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Manuel Leonardo Merz

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Gontran Sangouard

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Ganesh Kumar Mothukuri

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Mischa Schüttel

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Zsolt Bognár

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Cristina Díaz-Perlas

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Jonathan Vesin

    (Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Julien Bortoli Chapalay

    (Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Gerardo Turcatti

    (Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Laura Cendron

    (University of Padova)

  • Alessandro Angelini

    (Ca’ Foscari University of Venice
    European Centre for Living Technologies (ECLT), Ca’ Bottacin)

  • Christian Heinis

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

Abstract

Macrocycles have excellent potential as therapeutics due to their ability to bind challenging targets. However, generating macrocycles against new targets is hindered by a lack of large macrocycle libraries for high-throughput screening. To overcome this, we herein established a combinatorial approach by tethering a myriad of chemical fragments to peripheral groups of structurally diverse macrocyclic scaffolds in a combinatorial fashion, all at a picomole scale in nanoliter volumes using acoustic droplet ejection technology. In a proof-of-concept, we generate a target-tailored library of 19,968 macrocycles by conjugating 104 carboxylic-acid fragments to 192 macrocyclic scaffolds. The high reaction efficiency and small number of side products of the acylation reactions allowed direct assay without purification and thus a large throughput. In screens, we identify nanomolar inhibitors against thrombin (Ki = 44 ± 1 nM) and the MDM2:p53 protein-protein interaction (Kd MDM2 = 43 ± 18 nM). The increased efficiency of macrocycle synthesis and screening and general applicability of this approach unlocks possibilities for generating leads against any protein target.

Suggested Citation

  • Sevan Habeshian & Manuel Leonardo Merz & Gontran Sangouard & Ganesh Kumar Mothukuri & Mischa Schüttel & Zsolt Bognár & Cristina Díaz-Perlas & Jonathan Vesin & Julien Bortoli Chapalay & Gerardo Turcatt, 2022. "Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31428-8
    DOI: 10.1038/s41467-022-31428-8
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