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Synthesis and Screening of Macrocyclic Compound Libraries at a Nanomole-Scale
Abstract: Macrocycles hold great promise as a therapeutic modality due to their ability to bind challenging targets while often being able to cross membranes. However, the development of macrocycle-based ligands to new targets is not trivial. My laboratory at EPFL is developing new methods for the efficient synthesis and screening of large libraries comprising ten-thousands of macrocyclic compounds. We develop the macrocycles based on chemically and structurally highly diverse cyclic peptides having molecular weights below 700 Da and a limited polar surface to maximize the chances of membrane permeability. Importantly, we are tailoring the libraries to specific targets through incorporating building blocks having some affinity for the targets (e.g. amino acids, fragments), which is greatly increasing the chances of finding hits from libraries. In my talk, I will present a new approach that is based on nanoscale synthesis of sub-kDa macrocycles using acoustic dispensing and microplate-based screening (1, 2, 3). I will show examples of libraries, their screening, and nanomolar ligands developed against different proteins. |
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Related publications:
S. S., Kale, et al., Thiol-to-amine cyclization reaction enables screening of large libraries of macrocyclic compounds and the generation of sub-kilodalton ligands, Science Advances, 5, 8 (2019).
G. Sangouard, et al., Picomole-scale synthesis and screening of macrocyclic compound libraries by acoustic liquid transfer, Angewandte Chemie, 60, 40 (2021).
S. Habeshian, et al., Cyclative release strategy to obtain pure cyclic peptides directly from the solid phase, ACS Chemical Biology (2022).
S. S., Kale, et al., Thiol-to-amine cyclization reaction enables screening of large libraries of macrocyclic compounds and the generation of sub-kilodalton ligands, Science Advances, 5, 8 (2019).
G. Sangouard, et al., Picomole-scale synthesis and screening of macrocyclic compound libraries by acoustic liquid transfer, Angewandte Chemie, 60, 40 (2021).
S. Habeshian, et al., Cyclative release strategy to obtain pure cyclic peptides directly from the solid phase, ACS Chemical Biology (2022).
