Protein engineering of Neuregulin 1 to achieve receptor selectivity
Neuregulin-1 (NRG1) is a clinically validated target for biologics to treat heart failure. The EGF-like domain of NRG1 binds to ErbB4 or ErbB3 receptor leading to their trans-phosphorylation thereby signal transduction through receptor dimerization. Structure based protein engineering of NRG1 has been carried out to obtain selectivity for ErbB4 over ErbB3 (which is associated with reported adverse effect in the gastrointestinal tract). Protein variants from such structure-based design were produced recombinantly, and their properties were profiled by biophysical and biochemical assays. Selective NRG1 with different profiles have been obtained which can be used for further optimization.