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

Sevan Habeshian, Manuel Leonardo Merz, Gontran Sangouard, Ganesh Kumar Mothukuri, Mischa Schüttel, Zsolt Bognár, Cristina Díaz-Perlas, Jonathan Vesin, Julien Bortoli Chapalay, Gerardo Turcatti, Laura Cendron, Alessandro Angelini and Christian Heinis ()
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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
Christian Heinis: Ecole Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31428-8

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DOI: 10.1038/s41467-022-31428-8

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