Proteomimetic surface fragments distinguish targets by function. Issue 38 (21st September 2020)

• Record Type: Journal Article
• Authors: Tököli, Attila; Mag, Beáta; Bartus, Éva; Wéber, Edit; Szakonyi, Gerda; Simon, Márton A.; Czibula, Ágnes; Monostori, Éva; Nyitray, László; Martinek, Tamás A.
• Is Part Of: Chemical science. Volume 11:Issue 38(2020)
• Page Start: 10390
• Page End: 10398
• Publication Date: 2020-09-21
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d0sc03525d
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Foldameric local surface mimetics (LSMs) detect spots at protein surfaces and are promising building blocks in a fragment-centric design of xenobiotic structures and protein–protein interaction inhibitors. 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.