Developing drugs from the very beginning, especially for diseases with small number of patients, is extremely difficult. In contrast, the repositioning of approved drugs, whose safety information is already available, will allow us to bypass the slow drug developing process even for extremely rare diseases. The enzymatic activity of GNE is known to be activated by specific allosteric site mutations, raising a possibility that even the GNE with GNE- myopathy-causing mutations may possibly be activated by the modification of such allosteric sites. Our computationally predicted molecular model of GNE indicates the presence of a deep narrow cavity. Filling this cavity by a small compound is likely to inhibit the binding of CMP-NeuAc to the allosteric site, leading to the activation of the GNE.
In this study, we therefore aim to find approved small molecular agents that can fit the cavity and activate the GNE with either p.D207V in epimerase domain or p.V603L in kinase domain, which are the two most common mutations among Japanese GNE myopathy patients, by in silico drug screening based on binding affinity. We will then narrow down the candidates by measuring GNE enzyme activity and confirm the efficacy of drugs using patients’ cells including mutations frequent in other ethnic populations.
We propose the repositioning of approved drugs using in-silico approach is a fast, an effective and realistic method to treat GNE myopathy, which is the mission of NDF.