tRNA Synthetase Biology Platform
tRNA synthetases are ancient, essential proteins that have evolved novel domains to regulate diverse pathways extracellularly in humans. aTyr’s discovery platform is focused on unlocking hidden therapeutic intervention points by uncovering signaling pathways driven by its proprietary library of domains derived from all 20 tRNA synthetases.
Using efzofitimod, which is derived from a fragment of histidyl-tRNA synthetase (HARS) that selectively binds to neuropilin-2 (NRP2), as a model, we have developed a process to advance novel tRNA synthetase domains from concept to clinical product candidate. This process leverages our deep understanding of tRNA synthetase protein structure, gene splicing and tissue-specific regulation to identify potentially active protein domains. Screening approaches are employed to identify target cells and extracellular receptors for these tRNA synthetase-derived proteins. These cellular systems can be used in mechanism-of-action studies to elucidate the role these proteins play in cellular responses and their potential therapeutic utility.
Our dedicated team of scientists continue to make meaningful progress through internal efforts and our collaboration with Dualsystems Biotech AG in translating our unique platform into new tRNA synthetase-derived drug candidates for fibrosis and inflammation.
tRNA Synthetase-Derived Candidates
ATYR0101ATYR0101 is a fusion protein derived from a domain of aspartyl-tRNA synthetase (DARS). ATYR0101 binds directly to latent-transforming growth factor beta-binding protein 1 (LTBP1), which regulates transforming growth factor beta (TGFβ), which is at the apex of fibrotic signaling. Derived from a naturally occurring tRNA synthetase, ATYR0101 interacts with LTBP1 in a unique way that presents a differentiated approach to targeting fibrosis. Early data suggest ATYR0101 exerts its antifibrotic effects by inducing apoptosis of myofibroblasts in a TGFβ dependent manner. We believe ATYR010 may have broad therapeutic applications in multiple fibrotic diseases, such as pulmonary fibrosis, systemic sclerosis, and liver and kidney fibrosis.
ATYR0750ATYR0750 is a fusion protein derived from a domain of alanyl-tRNA synthetase (AARS). ATYR0750 is a novel ligand to fibroblast growth factor receptor 4 (FGFR4), which is involved in many cellular processes, including cell proliferation, differentiation and tissue repair. FGFR4 is known to play a role in diseases related to inflammation and fibrosis, particularly in the liver. As a novel ligand, ATYR0750 interacts with FGFR4 in a differentiated way to other approaches targeting the receptor, which may lead to improved therapeutic benefit.