Novel agonist of GDNF family ligand receptor RET for the treatment of experimental neuropathy

Abstract

Neuropathic pain is a chronic pain condition caused by lesion or disease affecting the somatosensory system. The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of NP and stimulate regeneration of sensory neurons in vivo. Here we report the development of the compound BT18 that selectively activates GFL receptors, alleviates pain and restores damaged dorsal root ganglion (DRG) neurons in rat models of NP. Significance statementNeuropathic pain (NP) is a chronic syndrome caused by different diseases and lesions affecting nervous system. Earlier studies demonstrated that neurotrophic factors -the glial cell line-derived neurotrophic factor (GDNF) and artemin -could reverse the damage done by lesions in animal models of NP. We demonstrate for the first time that a small molecule can activate receptor of GDNF and artemin, it alleviates pain symptoms in vivo in two animal models of NP and restores to normal the molecular markers expressed in sensory neurons. This compound, termed BT18, can pave way for creating novel disease modifying therapies for NP.

Molecular Dynamics Simulations of the Interactions between Glial Cell Line-Derived Neurotrophic Factor Family Receptor GFRα1 and Small-Molecule Ligands

“…The structure of ligand BT13 had been obtained through a high-throughput screening procedure; 5 compound BT18 is a further development of this structure. 6 We proceeded from a protein and two crystal structures on the GDNF–GFRα1 complex downloaded from Protein Data Bank (PDB). 16 The hybrid structural model of reconstituted mammalian GDNF–GFRα1–RetA complex (PDB code: 4UX8) had been derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data with a resolution 24.0 Å.…”

“… 6 Both compounds demonstrated efficacy in rat model of experimental neuropathy. 5 , 6 However, the molecular mechanism of the RET activation by the small-molecule ligands BT13 and BT18 remained unclear.…”

“…The aim of this study is therefore to explore the possible binding sites and interactions of a small-molecule ligand BT13 5 and its derivative BT18 6 ( Figure 1 ) with protein GFRα1 and GFRα1–RetA interface. These compounds are known to have an effect on GFRα1 and RetA functions.…”

“…These compounds are known to have an effect on GFRα1 and RetA functions. 5 , 6 Molecular dynamics (MD) simulations 8 − 10 may help to elucidate the binding site and time dynamics of interacting amino acid residues and to extend the information obtained from previous docking studies.…”

Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain and Parkinson’s disease

“…High-throughput screening of the libraries of chemical compounds led to the discovery of two classes of structurally unrelated selective RET agonists (Bespalov et al 2016;Sidorova et al 2017;Mahato et al 2019a, b;Jmaeff et al 2020). One class of these compounds, BT compounds, was shown to support the survival of naïve and toxin-challenged cultured dopamine neurons (Mahato et al 2019a) and promote neurite outgrowth from cultured sensory neurons (Sidorova et al 2017).…”