Generation of rationally-designed nerve growth factor (NGF) variants with receptor specificity

Nerve growth factor (NGF) is the prototypic member of the neurotrophin family and binds two receptors, TrkA and the 75 kDa neurotrophin receptor (p75NTR), through which diverse and sometimes opposing effects are mediated. Using the FoldX protein design algorithm, we generated eight NGF variants with different point mutations predicted to have altered binding to TrkA or p75NTR. Of these, the I31R NGF variant exhibited specific binding to p75NTR. The generation of this NGF variant with selective affinity for p75NTR can be used to enhance understanding of neurotrophin receptor imbalance in diseases and identifies a key targetable residue for the development of small molecules to disrupt binding of NGF to TrkA with potential uses in chronic pain. This material is based upon works supported by the Science Foundation Ireland under Grant No. 09/RFP/BMT2153, Enterprise Ireland (IP 2016 0480), the Higher Education Authority [PRTLI 5] and the Beckman Fund, School of Natural Sciences, NUI Galway, Ireland. peer-reviewed 2018-11-03