SARS cov2 spike trimer with ACE2 decoy
Any corona medicine - prophylactic or therapeutic - is only efficient against the virus variant that was used as template in development. If the virus invents an escape mutation, the antiviral effect is gone.
One thing is a must as long as infection starts with docking of the virus to the receptor ACE2: the virus has to recognize the binding part of the receptor. Now, if we inundate the mucous membranes of our respiratory tract with a substance closely mimicking the docking region of ACE2, we might prevent covid-19. So try antibodies (vaccination), but will they with their exessive specificity to exactly one viral strain also help against the next variant (e.g. δ)?
A group of researchers developed a protein similar to the ACE2 binding region, which blocks the viral binding region and thus prevents docking to the cellular receptor. The additional effect: a (future) viral mutant binding even stronger to ACE2 will also bind stronger to the decoy and thus kicks itself off.
The protein developed (called by the authors for reasons known to themselfes CTC-445.2) is not just a copy of the ACE2 binding region, for there are other condition to meet. The protein must be inert to humans (no provocation of an immune response), it must not be biochemically active (ACE2 produces a hormone regulating our blood pressure), upon synthesis it has to fold into the desired secondary structure and to keep the structure until medical application. The design of such a protein is a brain racking procedure, but protein structure comprehending computer programs aid the laboratory workers. The result is this in laboratory experiments active substance (all intermediates in the scientific course are listed in the publication cited below).
The most important structural elements are four helices and a short plated sheet called by the authors EE3 . Now about the contacts to the spike protein of the virus: two amino acids from the EE3-loop find binding partners in the virus . Most contacts are from helix H1 to binding partners in the spike . Helix 2 is also active . The purpose of helices 2-1 and 2-2 is to stabilize the whole CTC-445.2 protein. So the whole binding region of the spike protein is covered . In space filling view you may notice not a single hair will fit between spike and ACE2-decoy . In the model shown here all three spike proteins are covered by the ACE2-decoy, no matter whether the binding region is in the up or down position . This threefold occupation prevents reliably docking of the virus to "real" ACE2 . As with neutralizing nanobodies the "rubber band trick" may be applied: if one CTC-445.2 protein is connected to a second (or even third) molecule and thus upon binding of the first the others find their target much faster, the efficiency against a corona-infection is enhanced by several magnitudes. In vivo a nasal spray containing CTC-445.2 saved hamsters from a deadly cov2 challenge. Now volunteers for clinical studies are asked for.
T W Linsky et al, Science 370 (6521), 1208-1214 2020, DOI 10.1126/science.abe0075