Jing W, Procko E. ACE2-based decoy receptors for SARS coronavirus 2. Proteins. 2021 Sep;89(9):1065-1078.
As the COVID-19 pandemic continues, the SARS-CoV-2 virus is likely to become endemic with emerging novel variants, some of them seasonal. Updates to the various vaccines will be required, as will a range of anti-virals with a variety of mechanisms of action, for use in early infection and in hospitalizated patients, much like oseltamivir (Tamiflu) is used in certain populations for seasonal influenza. Monoclonal antibodies, such as those from Regeneron and GSK, directly bind the spike protein of the virus, thereby preventing entry into cells, reducing disease severity. However, these very effective treatments have not been able to treat all new variants of the virus, especially Omicron, and use of similar antibodies for endemic COVID would require new molecules and clinical trials as virus variants emerge. Therefore a pan-SARS-CoV-2-variant molecule capable of neutralizing the virus would be a key part of treatments in the future, alongside direct-acting small molecules such as Pfizer’s Paxlovid.
“THE BEST WAY TO PREDICT THE FUTURE
IS TO CREATE IT.”
Alan Kay Chief Computer Scientist from Atari
Cyrus is developing a modified version of the natural receptor that the virus uses to infect cells, ACE2, with drastically improved affinity for the virus. The wild-type ACE2 receptor can be expressed as a soluble protein (it is membrane-bound in most physiological circumstances), but it has much weaker affinity for the virus than the therapeutic antibodies, and therefore a higher affinity version is required in order to have similar therapeutic efficacy to the antibodies. Unlike the antibodies, though, a modified ACE2 should have very broad variant specificity, because variants with lower ACE2 binding that avoid the therapeutic would also be less infectious. Further, the ACE2 enzyme’s activity is associated with decreased lung damage in animal studies, providing a second mode of action beyond viral neutralization to prevent disease progression. Cyrus licensed the initial variant of ACE2 from the University of Illinois where Prof. Erik Procko’s lab discovered it via deep mutagenesis, and is carrying out pre-clinical work and computational protein engineering work to improve the drug-like qualities of the molecule and prepare it to enter IND-enabling studies and clinical trials.
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