Investigational drug works differently than antibody drugs which are losing effectiveness against the COVID-19 virus.
Scientists have developed a drug that potently neutralizes SARS-CoV-2, the COVID-19 coronavirus, and is equally effective against the Omicron variant and every other tested variant. The drug is designed in such a way that natural selection to maintain infectiousness of the virus should also maintain the drug’s activity against future variants.
The investigational drug was developed by researchers at Dana-Farber Cancer Institute. As described in a report published on December 7 in the journal Science Advances, the drug is not an antibody, but a related molecule known as an ACE2 receptor decoy. Unlike antibodies, the ACE2 decoy is far more difficult for the SARS-CoV-2 virus to evade because mutations in the virus that would enable it to avoid the drug would also reduce the virus’s ability to infect cells. The Dana-Farber scientists found a way to make this type of drug neutralize coronaviruses more potently in animals infected with COVID-19 and to make it safe to give to patients.
This report comes at a time when antibody drugs used to treat COVID-19 have lost their effectiveness because the viral spike protein has mutated to escape being targeted by the antibodies.
How ACE2 Decoys Inactivate the Virus
The researchers, led by first author James Torchia, MD, PhD, and senior author Gordon Freeman, PhD, identified features that make ACE2 decoys especially potent and long-lasting. For example, they found that when they included a piece of the ACE2 protein called the collectrin-like domain, it made the drug stick more tightly to the virus and have a longer life in the body. Their experiments showed that ACE2 decoys have potent activity against the COVID-19 virus because they trigger an irreversible change in the structure of the virus — they “pop” the top off the viral spike protein so it can’t bind to the cell-surface ACE2 receptor and infect cells.
The SARS-CoV-2 virus is covered with projections called spike proteins that enable the virus to infect cells. The spike protein binds to the ACE2 receptor on the cell surface and then refolds, driving the spike into the cell, enabling the virus to enter. ACE2 decoys lure the virus to bind to the decoy instead of the cell, “popping” the spike and inactivating the virus before it can enter cells. This explains the drug’s surprising potency: not only does it function as a competitive inhibitor, but it permanently inactivates the virus. Since binding to ACE2 is required for infection, variants can change but they must continue to bind to ACE2, making the drug persistently active against all variants.
The researchers say that, in addition to treating antibody-resistant variants of SARS-CoV-2, the drug described in this study could be useful to treat new coronaviruses that might emerge in the future to infect humans. This is because many coronaviruses in nature poised to enter the human population also utilize ACE2 to infect cells.
While the drug, called DF-COV-01, has not yet been tested in humans, manufacturing development is nearly complete and preclinical studies needed for regulatory approval are underway, with the goal of advancing the drug to clinical trials.
Reference: “Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo” by James A. Torchia, Alexander H. Tavares, Laura S. Carstensen, Da-Yuan Chen, Jessie Huang, Tianshu Xiao, Sonia Mukherjee, Patrick M. Reeves, Hua Tu, Ann E. Sluder, Bing Chen, Darrell N. Kotton, Richard A. Bowen, Mohsan Saeed, Mark C. Poznansky and Gordon J. Freeman, 7 December 2022, Science Advances.
DOI: 10.1126/sciadv.abq6527
This work was supported by a Department of Defense CDMRP Peer Reviewed Medical Research Program Technology/Therapeutic Development Award. Additional support was provided by a National Instititutes of Health grant, an Evergrande MassCPR award, and a grant from COVID-19 FastGrants.
The work was performed by a collaborative team including scientists from Dana-Farber Cancer Institute, Massachusetts General Hospital Vaccine and Immunotherapy Center, Boston University Aram V. Chobanian & Edward Avedisian School of Medicine, the National Emerging Infectious Disease Laboratory at Boston University, Colorado State University, and Boston Children’s Hospital.
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.
8 Comments
Shhh! Don’t tell Pfizer.
This sounds like something that should be warp-sped to market. But let’s see how many decades it takes to put together a human trial.
The article, ‘Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo’, by James Torchia, Alexander Tavares and others, states
“we find that ACE2-Fc decoys work by functionally mimicking cell-surface ACE2 to trigger refolding of the S protein from the pre- to postfusion state, resulting in dissociation of the S1 polypeptide from the S2 polypeptide. When the S protein refolds, the postfusion S2 remains on the surface of the virion but does not contain an RBD; therefore, it is no longer capable of binding cell-surface ACE2 and mediating infection. This ‘inactivation’ of the viral S protein by refolding could explain why ACE2 decoys potently neutralize SARS-CoV-2.”
“These findings demonstrate that ACE2 decoys can mimic cell-surface ACE2 and trigger dissociation of S1 from S2, resulting in a postfusion S2 polypeptide on the virion membrane that is no longer capable of binding cell surface ACE2.”
Torchia and Talvares use the word ‘postfusion’ several times to describe the SARS-Cov-2 S2 subunit, after ACE2-Fc decoy is attached to the Receptor Binding Motif. Are Torchia and Talvares using the word ‘postfusion’ S2 polypeptide, in the same manner that Gary Whittaker at Cornell University uses the word, ‘postfusion’?
“Class I fusion proteins catalyze the membrane fusion reaction though a sequence of states: (1) pre-fusion native state, (2) pre-fusion metastable state, (3) pre-hairpin intermediate state, (4) post-fusion stable state (Fig. 4).”, in the article ‘Coronavirus membrane fusion mechanism offers a potential target for antiviral development’, by Gary Whittaker, Tiffany Tang, Miya Bidon, and others, Cornell University
Does Torchia and Talvares ‘postfusion’ S2 polypeptide attain a postfusion ‘stable state’, after being disassociated from the spike S1 unit by ACE2-Fc decoy attach? Or, is the S2 polypeptide really in its prefusion native state? To attain true S2 subunit ‘postfusion’, Yongfei Cai, Jun Zhang and others observed,
”HR1 undergoes a ‘jackknife’ transition that can insert the fusion peptide (FP) into the target cell membrane. Folding back of HR2 places the FP and transmembrane (TM) segments at the same end of the molecule, causing the membranes with which they interact to bend toward each other, effectively leading to membrane fusion.” ,—– ‘Distinct conformational states of SARS-CoV-2 spike protein’, by Yongfei Cai, Jun Zhang, and others
Their Figure 5A shows (newly created) ‘postfusion’ spikes formed by the S2 subunits on the viron, after S1 subunits are disassociated from the S2 units.
“We suggest that both the prefusion and postfusion spikes are present on the surface of mature virion and the ratio between them may vary. A diagram of the virion is shown. The
postfusion spikes on the virion are formed by S2 after S1 dissociates in the absence of ACE2.”, in the article, ‘Distinct conformational states of SARS-CoV-2 spike protein’, by Yongfei Cai, Jun Zhang, and others
Did Torchia and Talvares see ‘postfusion’ spikes formed by the S2 subunits on the SARS-CoV-2 virons, after ACE2-Fc decoy caused the S1 subunits to be disassociated from the S2 units?
And, if Torchia and Talvares ‘postfusion’ S2 polypeptide was in a true ‘postfusion stable state’, would those S2 units be a candidate for what Gary Whittaker at Cornell University terms ‘Endosomal route (“late pathway”) entry into a human cell.
“3.2. Endosomal route (‘late pathway’)
In the absence of exogenous or membrane-bound proteases that enable entry at the plasma membrane surface, coronaviruses can be internalized via clathrin- and non-clathrin-mediated endocytosis (Inoue et al., 2007; Wang et al., 2008)……. Thus, it is believed that SARS-CoV, MERS-CoV, and SARS-CoV-2 dependency on low pH in the endosomal route is indirect; acidic conditions are required to activate cathepsin L protease, which in turn then act on S, resulting in a virus primed to undergo subsequent fusion steps.”, in the article, ‘Coronavirus membrane fusion mechanism offers a potential target for antiviral development’, by Whittaker, Tang, Bidon
Can ‘late pathway’ endosomal entry of ACE2-Fc decoy SARS-CoV-2 S2 subunits peptides into human cells be ruled out? And, to what extent does Torchia and Talvares ACE2-Fc decoy represent a DNA change to the human make-up? The regular ACE2 seems to be a DNA aspect of the human body.
“ACE2 maps to chromosome Xp22, spans 39.98 kb of genomic DNA, and contains 20 introns and 18 exons (Turner et al., 2002). The ACE2 gene encodes a type I membrane-bound glycoprotein composed of 805 amino acids (Marian, 2013) Functional domains include a C-terminal transmembrane anchoring region (carboxy-terminal domain), N-terminal signal peptide region……. S1 (of SARS-CoV-2) contains the receptor binding domain (RBD) and directly binds to the peptidase domain (PD) of ACE 2 to gain entry into host cells (Turner et al., 2002; Li et al., 2003; Yan et al., 2020)……It has been shown that the ACE2-Ang-(1-7)-MAS axis has a protective effect on the brain and prevents ischemic stroke (Jiang et al., 2013)……In addition to its protective role in the cardiovascular system, ACE2 has a direct protective role in alveolar epithelial cells. In the lungs ACE2 has numerous physiological functions, most of which are protective against lung injury”, in the article, ‘ACE2, Much More Than Just a Receptor for SARS-COV-2’, by Lobelia Samavati, and Bruce D. Uhal, Frontiers in Cellular and Infection Microbiology, June 2020 | Volume 10 | Article 317
To what extent will ACE2-Fc decoy interfere with the protective role of the regular ACE2 in the human body? And to what extent does ACE2-Fc decoy interact with the regular ACE2 genes, molecules and domains?
“the (regular) ACE2 CLD (a membrane-proximal collectrin-like domain that mediates ACE2 homodimerization) has been reported to improve the affinity of ACE2-Fc decoys for the S protein in vitro (18, 19, 23). However, it is unclear why this is the case since the CLD does not directly bind virus. It is also unknown whether inclusion of the CLD in an ACE2-Fc decoy has additional consequences for its function and whether it is important for in vivo antiviral activity. In addition, the mechanism by which ACE2 decoys neutralize
virus has yet to be thoroughly investigated”— ‘Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo’, by James Torchia, Alexander Tavares and others
The FDA and Atlanta CDC should love this ACE2-Fc decoy vaccine.
In Christ Jesus
Great set of questions Gutierrez! I am going to link to the article here, in an article I wrote regarding CJD and Prion Disease earlier in the pandemic. I’ll be encouraging readers to look for your particular response, because this issue of folding or refolding proteins can have far-reaching effects!
Bill Gates may be quite interested in this new technology that can be used to make pan-flu virus vaccines that he has been endeavoring for years.
I bet this will eventually be the cure for the the flew as it is also a coronavirus.
NO. Influenza virus and coronavirus are 2 separate types of virals each with their own strains.
Can we use this same technology to find a “cure’ for those, like myself, suffering from COVID vaccine side effects? It seems through what little research we have on covid vaccine reaction that the spike protein is continually replicating. It has been found in my non-classical monocytes. The vaccine injured community also has very high titers with those that have never had a live infection. We are willing and ready to be researched in depth, and find the mystery to these neurologic, autonomic, and cardiac reactions. The vaccine injured are MANY, and we are ready to find our relief. For some of us, it has been 2 years. We would love to help! Please visit react19.org and realnotrare.com
But ACE2 is not simply an “receptor” (that is just what it does to the virus particles), it is an enzyme that modifies angiotensin, thus regulating the blood pressure and other things in the body. Can we exclude that the new drug reacts with angiotensin (either actively or just as a competitor)?