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Protein‐Templated Hit Identification through an Ugi Four‐Component Reaction **
Author(s) -
Mancini Federica,
Unver M. Yagiz,
Elgaher Walid A. M.,
Jumde Varsha R.,
Alhayek Alaa,
Lukat Peer,
Herrmann Jennifer,
Witte Martin D.,
Köck Matthias,
Blankenfeldt Wulf,
Müller Rolf,
Hirsch Anna K. H.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002250
Subject(s) - ugi reaction , combinatorial chemistry , chemistry , protease , drug discovery , mass spectrometry , identification (biology) , computational biology , enzyme , biophysics , biochemistry , stereochemistry , chromatography , biology , isocyanide , botany
Kinetic target‐guided synthesis represents an efficient hit‐identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β‐sliding clamp DnaN, respectively. Highly sensitive mass‐spectrometry methods enabled monitoring of the protein‐templated reaction of four complementary reaction partners, which occurred in a background‐free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN. The Ugi products we identified show low micromolar activity on endothiapepsin or moderate affinity for the β‐sliding clamp. We succeeded in expanding the portfolio of chemical reactions and biological targets and demonstrated the efficiency and sensitivity of this approach, which can find application on any drug target.