We follow a bottom-up fragment-centric development of biomimetic compounds. First, short protein surface mimetic sequences are selected, which can bind weakly to the target protein. Then, the small proteomimetic building blocks are linked together, thus achieving stronger binding (lower K_D). To select the best multivalent ligands, we use system chemistry approaches e.g. protein-templated dynamic combinatorial libraries under thermodynamic control. In these systems, molecular recognition transfers the structural information to the ligands and the building of high-affinity multivalent ligands is amplified.

Chemical evolution was a prolonged process before life emerged and led to the development of complex macromolecules. However, potential “criteria for life” such as the ability to replication, mutation and selection, can be interpreted at the level of molecules, too. Chemical evolution-based molecular systems work far from equilibrium and require external energy input to cover entropy production. Thus, they can be even more efficient methods for ligand maturation than classic dynamic combinatorial libraries based on thermodynamic equilibrium. We have constructed a UV light-fuelled chemical network with primitive biomimetic peptidic foldamer components displaying sequence-dependent replication and replicator decomposition. We have adapted this system for ligand development, using the target protein as a selection factor (template).

Selected publications

Light-fuelled primitive replication and selection in evolvable biomimetic chemical networks. Bartus, É.; Tököli, A.; Mag, B.; Bajcsi, Á.; Kecskeméti, G.; Wéber, E.; Kele, Z.; Fenteany, G.; Martinek, T. A. J. Am. Chem. Soc. 2023, 145, 13371-13383.

De Novo Modular Development of a Foldameric Protein–Protein Interaction Inhibitor for Separate Hot Spots: A Dynamic Covalent Assembly Approach. Bartus, É.; Hegedüs, Z.; Wéber, E.; Csipak, B.; Szakonyi, G.; Martinek, T. A. ChemistryOpen 2017, 6 (2), 236–241.