Inosine

Inosine is a natural purine nucleoside that commonly occurs in transfer RNAs in humans. The molecule consists of hypoxanthine connected to a ribofuranose ring via a glycosidic bond. It is a degradation product of adenosine.

Elsewhere in nature, inosine is found in red meat, pork, and poultry. Its 5’-monophosphate is associated with the flavor and taste of red and white meats.

In 1910 chemists Phoebus A.T. Levene and Walter A. Jacobs at the Rockefeller Institute of Medical Research in New York City (now Rockefeller University) synthesized inosine by treating adenosine with sodium nitrate and acetic acid. Later (in 1947), using less harsh conditions, Herman M. Kalckar at the Public Health Institute of the City of New York prepared inosine by incubating adenosine with intestine-based adenosine deaminase.

Since 2000, inosine has been tried as a treatment for medical conditions such as Parkinson’s disease, multiple sclerosis, stroke, and spinal cord injuries. None of these efforts produced a commercial drug. But earlier this year, inosine turned up in an off-target result generated by a CRISPR-based gene editor.

David R. Liu and collaborators at the Broad Institute of Harvard and MIT (Cambridge, MA) and Harvard University found that an adenine base editor (ABE) that efficiently converts targeted A–T base pairs in genomic DNA to G–C pairs does not do so well when it edits cellular RNAs. The editor, called ABEmax, generates a low but significant amount of inosine from the adenosine in RNA. The authors do not know whether the error will have any biological effects. But they note that some cancers evaded immune checkpoint inhibitors when similar results occurred in other RNA studies.