Azadyne have identified a new target and previously undrugged pathway. Using this approach, Azadyne are able to exert epigenetic control over tRNA.
Azadyne’s research has focused on the exploitation of the queuine tRNA ribosyltransferase (QTRT) enzyme pathway (also known as TGT), characterised by the founders (Boland et al., 2009; Chen et al., 2010).
Queuine is a natural micronutrient that is produced exclusively by bacteria. Structurally, it has a 7- deazaguanine core (turquoise), an amino-methyl side chain (green) and a cyclopentenediol ring (red) shown below. Almost all eukaryotic organisms (mammals, algae, fungi, yeast, and plants) salvage queuine from bacteria. Humans obtain it from ingested food and the gut flora.
Following uptake into cells, queuine is incorporated into the anticodon loop of transfer RNA (tRNA) associated with the amino acids, tyrosine, histidine, aspartic acid and asparagine: referred to as GUN tRNAs; shown below. In an unusual reaction, the nuclear encoded guanine at position 34 of the anticodon loop is replaced by queuine. This reaction is carried out by the queuine tRNA ribosyltransferase (QTRT) enzyme; also referred to as TGT (tRNA- guanine transglycosylase) or QI (queuine insertase) (Alqasem et al., 2020). Almost all eukaryotes perform this reaction.
Under certain conditions, tRNA in that cell is unmodified by queuine.
Azadyne have designed small molecule queuine analogs which are substrates for the QTRT enzyme and which can be selectively inserted into the unmodified tRNA of these cells.
With Azadyne’s proprietary knowledge of the pathway we are able to provide compounds carefully designed and calibrated to induce effects within the cells.
Portfolio
MS-19-16 preclinical autoimmune
MS-19-17 preclinical autoimmune
Aza – B preclinical – other indication