Cardiac Troponin I (cTnI) is a clinically relevant biomarker of acute myocardial infarction (AMI). cTnI-binding affinity ligands therefore have potential utility in the development of diagnostic assays and platforms for therapeutics development. In this talk, we will describe a strategy for the design and discovery of affinity peptides for cTnI from its natural ligands. Our approach is guided by protein-protein interactions in natural systems and focuses on the hetero-trimeric complex of cardiac troponin T (cTnT), C (cTnC) and cTnI. cTnC and cTnT, owing to their innate ability to bind cTnI, are potential templates for the design of cTnI-binding peptides. As shown in Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/240nm/uploads/43366_hkr.jpg' alt='' />, relying on the primary sequences of cTnC and cTnT, we designed a library of short overlapping peptides that span the entirety of cTnC and cTnT and tested them for binding to cTnI. We were successful in identifying several peptides that display high affinity (1-100 nM) for cTnI. The specific implication of this work is that mimicking natural protein-protein interactions is an excellent starting point for the discovery and rational design of peptide ligands. The knowledge of secondary or tertiary structures of the proteins involved is not a necessary pre-condition. This approach is broadly applicable to any protein with at least one natural binding ligand with known primary sequence. For proteins with multiple natural ligands, this approach can potentially yield several distinct affinity peptides capable of simultaneously binding the target protein at complementary interfaces.

Design of affinity peptides from natural protein ligands: A case study of the cardiac troponin complex

247th National Meeting (2014)

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