Synthetic protein hints at flu treatment


Reintroducing a protein lost through evolution holds promise for reducing the effects of viral infections. Andrew Masterson reports.


An orangutan.
Unlike chimpanzees, gorillas and humans, orang-utans still have the ability to produce an analogue of the flu-fighting protein RC-101.
Robertus Pudyanto / Getty

A synthesised protein shows promise for reducing the symptoms, and perhaps lethality, of influenza, research from the University of Maryland school of medicine, in the US, suggests.

In a paper published in the Journal of Leukocyte Biology, scientists report that the protein, dubbed retrocyclin-101 (RC-101), reduced influenza viral load and its associated inflammation when tested on live mice and human cell-lines.

“We think that this protein could lead to medicines that could be a powerful tool in the battle against this disease, and against inflammation in general,” says primary author Daniel Prantner.

RC-101 is a novel type of “defensin”, a form of protein found in most animals and some plants. Defensins act against bacteria, fungi and viruses.

It was first formulated as an anti-viral agent in 2004, when it was derived from a naturally occurring type of defensin (known as RTD) found in rhesus macaque monkeys. It was found to provoke promising immune responses to HIV.

Humans possess genes technically able to express retrocyclin-type defensin proteins, but a sequence mutation prevents them ever maturing. A retrocyclin precursor manufactured by human pseudogenes has been identified as playing a role in protecting white blood cells from infection by certain strains of HIV.

By adjusting retrocyclin proteins one amino acid at a time, a team led by Sherry Owen of the US Centres for Disease Control created RC-101, which showed promise in modulating the activities of other proteins in attacking HIV-1.

In a paper published in the journal AIDS Research and Human Retroviruses, Owen and colleagues concluded that “the performance of RC-101 suggests that additional ‘engineering’ could further enhance” the abilities of human defensins.

A more recent study, in 2016, reported that RC-101 was able to “destabilise” the toxins in a range of viruses, including HIV and the commonly used lab-test viruses Tobacco Etch (TEV) and Prototype Foamy (PFV).

In the most recent research Prantner and his team tested RC-101 against a flu virus. The scientists found that in mice and in human cell-lines the novel peptide influenced another protein, toll-like receptor-4 (TLR-4), which plays a leading role in the recognition of pathogens.

As a result, the influenza virus was substantially blocked from invading cells, and the inflammation that causes most flu symptoms – such as aches and high temperatures – was also suppressed.

In a mouse test, two cohorts were infected with flu, with one then given RC-101. This group experienced a 20% fatality rate (and milder symptoms in the remainder) while 90% of the control group died.

The inability of humans to produce a defensin analogue of RC-101 appears to be the result of comparatively recent evolution. Chimpanzees and gorillas are similarly bereft, but orangutans still make it.

The success of RC-101 against influenza provides a clear road forward for further research into a potential treatment for the disease, which kills thousands around the world every year. Prantner and his colleagues also intend to test the protein against other viral infections, including dengue and Zika.

  1. https://www.ncbi.nlm.nih.gov/pubmed/28729359
  2. https://www.ncbi.nlm.nih.gov/pubmed/28729359
  3. http://online.liebertpub.com/doi/abs/10.1089/aid.2004.20.1157
  4. http://online.liebertpub.com/doi/abs/10.1089/aid.2004.20.1157
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007486/
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