TY - JOUR

T1 - Large Libraries of Structurally Diverse Macrocycles Suitable for Membrane Permeation

AU - Nielsen, Alexander L.

AU - Bognar, Zsolt

AU - Mothukuri, Ganesh K.

AU - Zarda, Anne

AU - Schüttel, Mischa

AU - Merz, Manuel L.

AU - Ji, Xinjian

AU - Will, Edward J.

AU - Chinellato, Monica

AU - Bartling, Christian R.O.

AU - Strømgaard, Kristian

AU - Cendron, Laura

AU - Angelini, Alessandro

AU - Heinis, Christian

N1 - Publisher Copyright: © 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

PY - 2024

Y1 - 2024

N2 - Macrocycles offer an attractive format for drug development due to their good binding properties and potential to cross cell membranes. To efficiently identify macrocyclic ligands for new targets, methods for the synthesis and screening of large combinatorial libraries of small cyclic peptides were developed, many of them using thiol groups for efficient peptide macrocyclization. However, a weakness of these libraries is that invariant thiol-containing building blocks such as cysteine are used, resulting in a region that does not contribute to library diversity but increases molecule size. Herein, we synthesized a series of structurally diverse thiol-containing elements and used them for the combinatorial synthesis of a 2,688-member library of small, structurally diverse peptidic macrocycles with unprecedented skeletal complexity. We then used this library to discover potent thrombin and plasma kallikrein inhibitors, some also demonstrating favorable membrane permeability. X-ray structure analysis of macrocycle-target complexes showed that the size and shape of the newly developed thiol elements are key for binding. The strategy and library format presented in this work significantly enhance structural diversity by allowing combinatorial modifications to a previously invariant region of peptide macrocycles, which may be broadly applied in the development of membrane permeable therapeutics.

AB - Macrocycles offer an attractive format for drug development due to their good binding properties and potential to cross cell membranes. To efficiently identify macrocyclic ligands for new targets, methods for the synthesis and screening of large combinatorial libraries of small cyclic peptides were developed, many of them using thiol groups for efficient peptide macrocyclization. However, a weakness of these libraries is that invariant thiol-containing building blocks such as cysteine are used, resulting in a region that does not contribute to library diversity but increases molecule size. Herein, we synthesized a series of structurally diverse thiol-containing elements and used them for the combinatorial synthesis of a 2,688-member library of small, structurally diverse peptidic macrocycles with unprecedented skeletal complexity. We then used this library to discover potent thrombin and plasma kallikrein inhibitors, some also demonstrating favorable membrane permeability. X-ray structure analysis of macrocycle-target complexes showed that the size and shape of the newly developed thiol elements are key for binding. The strategy and library format presented in this work significantly enhance structural diversity by allowing combinatorial modifications to a previously invariant region of peptide macrocycles, which may be broadly applied in the development of membrane permeable therapeutics.

KW - cell permeability

KW - cyclization

KW - high-throughput screening

KW - macrocycle

KW - protease inhibitor

U2 - 10.1002/anie.202400350

DO - 10.1002/anie.202400350

M3 - Journal article

C2 - 38602024

AN - SCOPUS:85193908091

VL - 63

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

SN - 1433-7851

IS - 26

M1 - e202400350

ER -