Conformationally constrained peptides hold promise as molecular tools in chemical biology and as a new modality in drug discovery. The construction and screening of a target-focused library could be a promising approach for the generation of de novo ligands or inhibitors against target proteins. Here, we have prepared a protein kinase-focused library by chemically modifying helix-loop-helix (HLH) peptides displayed on phage and subsequently tethered to adenosine. The library was screened against aurora kinase A (AurA). The selected HLH peptide Bip-3 retained the α-helical structure and bound to AurA with a K value of 13.7 μM. Bip-3 and the adenosine-tethered peptide Bip-3-Adc provided IC values of 103 μM and 7.7 μM, respectively, suggesting that Bip-3-Adc bivalently inhibited AurA. In addition, the selectivity of Bip-3-Adc to several protein kinases was tested, and was highest against AurA. These results demonstrate that chemical modification can enable the construction of a kinase-focused library of phage-displayed HLH peptides.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9297947 | PMC |
| http://dx.doi.org/10.1002/cbic.202100450 | DOI Listing |
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