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Issue 38, 2020
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Proteomimetic surface fragments distinguish targets by function

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Abstract

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

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Supplementary files

Article information


Submitted
25 Jun 2020
Accepted
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

Chem. Sci., 2020,11, 10390-10398
Article type
Edge Article

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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