In vivo modification of tRNA with an artificial nucleobase leads to full disease remission in an animal model of multiple sclerosis.
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Varghese S, Cotter M, Chevot F, Fergus C, Cunningham C, Mills KH, Connon SJ, Southern JM, Kelly VP
In vivo modification of tRNA with an artificial nucleobase leads to full disease remission in an animal model of multiple sclerosis.
Nucleic Acids Res. 2017 Feb 28;45(4):2029-2039. doi: 10.1093/nar/gkw847.
- PubMed ID
- 28204548 [ View in PubMed]
- Abstract
Queuine is a modified pyrrolopyrimidine nucleobase derived exclusively from bacteria. It post-transcriptionally replaces guanine 34 in transfer RNA isoacceptors for Asp, Asn, His and Tyr, in almost all eukaryotic organisms, through the activity of the ancient tRNA guanine transglycosylase (TGT) enzyme. tRNA hypomodification with queuine is a characteristic of rapidly-proliferating, non-differentiated cells. Autoimmune diseases, including multiple sclerosis, are characterised by the rapid expansion of T cells directed to self-antigens. Here, we demonstrate the potential medicinal relevance of targeting the modification of tRNA in the treatment of a chronic multiple sclerosis model-murine experimental autoimmune encephalomyelitis. Administration of a de novo designed eukaryotic TGT substrate (NPPDAG) led to an unprecedented complete reversal of clinical symptoms and a dramatic reduction of markers associated with immune hyperactivation and neuronal damage after five daily doses. TGT is essential for the therapeutic effect, since animals deficient in TGT activity were refractory to therapy. The data suggest that exploitation of the eukaryotic TGT enzyme is a promising approach for the treatment of multiple sclerosis.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Queuine Queuine tRNA-ribosyltransferase Protein Zymomonas mobilis subsp. mobilis (strain ATCC 31821 / ZM4 / CP4) UnknownSubstrateDetails