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Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale.
Habeshian, Sevan; Merz, Manuel Leonardo; Sangouard, Gontran; Mothukuri, Ganesh Kumar; Schüttel, Mischa; Bognár, Zsolt; Díaz-Perlas, Cristina; Vesin, Jonathan; Bortoli Chapalay, Julien; Turcatti, Gerardo; Cendron, Laura; Angelini, Alessandro; Heinis, Christian.
Affiliation
  • Habeshian S; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
  • Merz ML; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
  • Sangouard G; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
  • Mothukuri GK; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
  • Schüttel M; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
  • Bognár Z; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
  • Díaz-Perlas C; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
  • Vesin J; Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Bortoli Chapalay J; Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Turcatti G; Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Cendron L; Department of Biology, University of Padova, 35131, Padova, Italy.
  • Angelini A; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Via Torino 155, Venezia Mestre, Venice, 30172, Italy.
  • Heinis C; European Centre for Living Technologies (ECLT), Ca' Bottacin, Dorsoduro 3911, Calle Crosera, Venice, 30124, Italy.
Nat Commun ; 13(1): 3823, 2022 07 02.
Article in En | MEDLINE | ID: mdl-35780129
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cyclization Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: Switzerland Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cyclization Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: Switzerland Country of publication: United kingdom