Issue 38, 2020

Proteomimetic surface fragments distinguish targets by function


The fragment-centric design promises a means to develop complex xenobiotic protein surface mimetics, but it is challenging to find locally biomimetic structures. To address this issue, foldameric local surface mimetic (LSM) libraries were constructed. Protein affinity patterns, ligand promiscuity and protein druggability were evaluated using pull-down data for targets with various interaction tendencies and levels of homology. LSM probes based on H14 helices exhibited sufficient binding affinities for the detection of both orthosteric and non-orthosteric spots, and overall binding tendencies correlated with the magnitude of the target interactome. Binding was driven by two proteinogenic side chains and LSM probes could distinguish structurally similar proteins with different functions, indicating limited promiscuity. Binding patterns displayed similar side chain enrichment values to those for native protein–protein interfaces implying locally biomimetic behavior. These analyses suggest that in a fragment-centric approach foldameric LSMs can serve as useful probes and building blocks for undruggable protein interfaces.

Graphical abstract: Proteomimetic surface fragments distinguish targets by function

Supplementary files

Article information

Article type
Edge Article
25 Jun 2020
09 Sep 2020
First published
10 Sep 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2020,11, 10390-10398

Proteomimetic surface fragments distinguish targets by function

A. Tököli, B. Mag, É. Bartus, E. Wéber, G. Szakonyi, M. A. Simon, Á. Czibula, É. Monostori, L. Nyitray and T. A. Martinek, Chem. Sci., 2020, 11, 10390 DOI: 10.1039/D0SC03525D

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