If you’ve not heard, llama antibodies are a bit magical. Having been a serious contender as a Covid-19 treatment, they’ve also provided clues for creating a universal flu vaccine. Now, new research published in the journal Nature Methods has created a synthetic antibody inspired by llamas to stop the human body from destroying imperfect, but still functional proteins. The novel technology could be used to treat several conditions including cystic fibrosis, cancer and epilepsy.
Many genetic diseases result in mutated proteins being churned out by our cells, and while some of these are still able to carry out their function our bodies will ultimately destroy them. The imperfect proteins are marked by our cell’s quality control system with a peptide called ubiquitin. While this is a necessary cell function, preventing these proteins from being destroyed can sometimes be beneficial as while they are imperfect some are still capable of doing their job. Deubiquitinase enzymes (DUBs) can be employed to remove the “for destruction” tags but allowing them to remove tags from all imperfect proteins would be harmful and so such therapies need to be targeted.
Here is where our magical llama antibodies come into play, as study authors Henry Colecraft and his student, Scott Kanner, identified a means of targeting DUBs using nanobodies. Nanobodies are tiny antibodies which are produced by llamas, camels and alpacas, and they bind with their targets with uniquely reliable specificity. They are used in place of antibodies because antibodies’ function changes when acting inside cells, unlike nanobodies.
The new technology is called engineered deubiquitinases (enDUBs for short, not to be confused with the late-noughties hip hop group N-Dubz) and it uses a synthetic nanobody that is able to recognize and de-tag specific proteins.
So far, two enDUBs have been taken for a test drive saving the imperfect proteins churned out by the cells of people with cystic fibrosis and long QT syndrome, a genetic disease characterized by arrhythmias and sudden death. The new technology comes with an added perk as specializing the enDUBs can be done without having to inject target proteins into living animals as has been the practice. Instead, they were able to find the right binders by sifting through millions of nanobodies stored in a synthetic yeast nanobody display library, the archival membership we never knew we needed.
Both test drives proved successful, seeing the modified enDUBs targeting the correct mutated proteins and untagging the ubiquitin that would’ve otherwise seen them destroyed. The salvaged imperfect proteins then migrated to their correct position on the cell membrane and carried out their expected function.
"In the case of one of the cystic fibrosis proteins we tested, we get a remarkable rescue, restoring protein levels in the cell membrane to about 50% of normal," Colecraft said in a statement. "If that happened in a patient, it would be transformative.
"The approach can be applied to any protein in the cell, not just membrane proteins or proteins altered by genetic mutations. It could be applicable to any disease where protein degradation is a factor, including cancer and epilepsy."
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