Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis

Abstract

The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPCneuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents.

Functional genomic analyses highlight a shift in Gpr17‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

“…By binding to Gpr17, inflammatory molecules could disrupt stage‐dependent Gpr17 regulatory mechanisms, thus resulting in impaired COP terminal maturation and myelination. Since Gpr17 is expressed on the cell membrane, and thus amenable for pharmacological manipulation, we envisage that novel selective molecules directly acting at the Gpr17 receptor level could revert ageing associated effects on myelination (Parravicini et al, 2020). Notably, in line with the above findings and with Gpr17 function as a sensor for brain damage (Lecca et al, 2008), antagonism of Gpr17 has a rejuvenation effect in the ageing brain (Marschallinger et al, 2015).…”

“…we did not specifically assess the rejuvenating effects of ligands directly acting on Gpr17 (Parravicini et al, 2020), which will represent the focus of future studies.…”

Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives

“…Indeed, the selective GPR17 agonist Asinex 1 promoted OPC maturation and myelination of dorsal root ganglion (DRG) neurons in vitro [ 202 ]. Of note, a recent in vivo study showed that the treatment with another selective agonist, named galinex, resulted in protection against EAE symptoms exacerbation [ 203 ].…”

Strategies for Oligodendrocyte and Myelin Repair in Traumatic CNS Injury

“…Another family of GPCRs that has received increasing attention is the GPR17 receptors, which act as sensors of local damage to the myelin sheath. Modification of GPR17 activity promotes oligodendroglial maturation in vitro and in animal models (Merten et al, 2018 ; Dziedzic et al, 2020 ; Parravicini et al, 2020 ). Finally, the protective effects of pregnancy on MS relapse have led to the extensive focus on the estrogen receptor (ER) and its ligands as a means for promoting remyelination (Xiao et al, 2012 ; Moore et al, 2014 ; Najm et al, 2015 ; Itoh et al, 2017 ).…”