'Decoy' Protein Offers New Treatment Approach For Covid-19.

(Posted on Wednesday, February 2, 2022)

The rise of immune-evasive variants like omicron, and breakthrough infections along with it, has foregrounded the need for antiviral therapies. Particularly antiviral therapies that can stand up to multiple different variants without succumbing to resistance. Researchers at the University of Illinois Chicago have just taken a step in that direction, developing and testing a “decoy” protein that tricks SARS-CoV-2 into binding to it instead of to host cells.

SARS-CoV-2 infects us by binding to angiotensin-converting enzyme 2 (ACE2). Located on its outer surface, the virus’ Spike proteins latch onto our ACE2 receptors, which act like cellular doorways of sorts, allowing the virus to enter our cells.

Given the importance of this interaction, many variants of concern exhibit mutations to their spike protein that improve their ability to bind to ACE2. Mutations that interfere with the binding process would hinder the variant’s ability to replicate, reducing transmissibility and viral fitness more generally. So, most variants are primed to “recognize” and bind to ACE2.

By extension, they are also primed to bind with anything structurally similar to ACE2.

Zhang et al. took advantage of this by engineering artificial ACE2 proteins that mimic human ACE2. The engineered decoys are designed with three amino acid substitutions—T27Y, L79T and N330Y— which improve how strongly they can bind to SARS-CoV-2’s spike protein: a full 35-fold increase in binding strength when compared to unmutated human ACE2.

The drug treatment works by allowing these extra “sticky” engineered ACE2 proteins to compete with human ACE2 in a race to bind to SARS-CoV-2’s Spike protein. Because of their heightened binding affinity, the decoys win out (Figure 1).

This was reflected in vivo by tests the researchers performed on mice. Usually mice aren’t a good measure of Covid-19-related injury since their ACE2 receptors don’t bind well with the Spike proteins of SARS-CoV-2. To circumvent this issue, Zhang et al. used mice that express human ACE2 instead, more accurately modeling the disease progression and damage one would see in humans.

They infected the mice with SARS-CoV-2 and then split them into three groups: a control group that received nothing, a group that received the ACE2 decoy 12 hours post-infection, and another that received it 24 hours post-infection. The treatment was delivered intravenously daily for a period of seven days. After two weeks, all of the mice in the control group had died, showing a 30% weight loss. Both treatment groups, on the other hand, boasted survival rates of 50 – 60%, with marked reduction in lung damage and no signs of severe acute respiratory syndrome. Fourteen days post-infection, the treated mice were back to normal.

In vitro results showed that the engineered ACE2 also remained effective against the alpha, beta, gamma, and delta variants of concern, maintaining a tight bond with their respective Spike proteins. Omicron had not yet come onto the scene during these trials.

To make sure these results carried over to live infection, Zhang et al. exposed mice to the gamma variant. Again, all of the mice in the control group died. The mice that received treatment 24 hours post-infection did not fare much better, their death only delayed but not avoided. Treatment at 12 hours post-infection, however, brought about a 50-60% reduction in death and a return to full health 14 days post-infection.

“Considering the emergence of omicron, it is very good news that the ACE2 decoy was able to bind and neutralize several variants, and this reinforces the potential of this drug as a treatment, including against new or future variants of the virus,” said Jalees Rehman, co-lead author of the study.

Aside from its ability to remain effective against variants, the engineered ACE2 protein has two other advantages: it can be delivered through inhalation and it can be used as a pre-exposure prophylactic. Intranasal administration significantly reduces time and cost when compared to intravenous delivery and pre-exposure use could help immunocompromised individuals preemptively boost their immune systems, albeit temporarily.

Hopefully the results from these mouse models can be replicated in human trials; after all, this engineered ACE2 decoy seems to offer us another promising approach to Covid-19 treatment. The more interventions we have available to us, the more varied and tailored we can make our treatment plans, and the less likely we are to be confronted with viral resistance.

Read the full article on Forbes.