COVID-19 Latest: Study Identifies Factor D Inhibitor (ACH-145951) That Can Inhibit Direct Activation Of The Alternative Complement Pathway By SARS-CoV-2
: Researchers from John Hopkins have identified a compound known as factor D Inhibitor(ACH-145951) that can inhibit the alternative complement immune pathway system that is activated by the SARS-CoV-2 spike protein. Blocking this immune system pathway may stop COVID-19 Infection and prevent severe organ damage.
Animal models demonstrating end-organ protection in C3 deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear.
To summarize, in this research, the study team demonstrates that SARS-CoV-2 spike protein (subunit 1 and 2), but not N protein, directly activates the alternative pathway of complement (APC). Complement dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGA
null target cells, and complement factor Bb is increased in the supernatant from spike protein treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert non-activator surfaces to activator surfaces by preventing the inactivation of the cell surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro
but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.
The study results are published in the peer reviewed journal: Blood, a journal of the American Society of Hematology. https://ashpublications.org/blood/article/doi/10.1182/blood.2020008248/463611/Direct-activation-of-the-alternative-complement
The study team from John Hopkins believes that the key to one possibility of stopping the SARS-CoV-2 from attaching the human host is by blocking a protein that enables the virus to turn the immune system against healthy cells
From the results of their study findings, the study team believes that inhibiting the protein, known as factor D, also will curtail the potentially deadly inflammatory reactions that many patients have to the SARs-CoV-2 coronavirus.
Even more interesting in the discovery is that there may already be drugs in development and testing for other diseases that can do the required blocking.
Researchers already know that spike proteins on the surface of the SARS-CoV-2 virus that make the pathogen look like the spiny ball from a medieval mace, are the means by which it attaches to cells targeted for infection.
In order to do this, the spikes first grab hold of heparan sulfate, a large, complex sugar molecule found on the surface of cells in the lungs, blood vessels and smooth muscle making up most organs. Facilitated by its ini
tial binding with heparan sulfate, SARS-CoV-2 then uses another cell-surface component, the protein known as angiotensin-converting enzyme 2 (ACE2), as its doorway into the attacked cell.
The study team discovered that when SARS-CoV-2 ties up heparan sulfate, it prevents factor H from using the sugar molecule to bind with cells. Factor H’s normal function is to regulate the chemical signals that trigger inflammation and keep the immune system from harming healthy cells. Without this protection, cells in the lungs, heart, kidneys and other organs can be destroyed by the defense mechanism nature intended to safeguard them.
Study senior author Dr Robert Brodsky, M.D., director of the hematology division at the Johns Hopkins University School of Medicine told Thailand Medical News, “Previous research has suggested that along with tying up heparan sulfate, SARS-CoV-2 activates a cascading series of biological reactions what we call the alternative pathway of complement, or APC that can lead to inflammation and cell destruction if misdirected by the immune system at healthy organs. The goal of our study was to discover how the virus activates this pathway and to find a way to inhibit it before the damage happens.”
The alternative pathway of complement, or APC is one of three chain reaction processes involving the splitting and combining of more than 20 different proteins known as complement proteins that usually gets activated when bacteria or viruses invade the body.
Typically the end product of this complement cascade, a structure called membrane attack complex (MAC), forms on the surface of the invader and causes its destruction, either by creating holes in bacterial membranes or disrupting a virus’ outer envelope.
However, MACs also can arise on the membranes of healthy cells. Fortunately, humans have a number of complement proteins, including factor H, that regulate the APC, keep it in check and therefore, protect normal cells from damage by MACs.
In various studies Dr Brodsky and his colleagues used normal human blood serum and three subunits of the SARS-CoV-2 spike protein to discover exactly how the virus activates the APC, hijacks the immune system and endangers normal cells.
The study team discovered that two of the subunits, called S1 and S2, are the components that bind the virus to heparan sulfate setting off the APC cascade and blocking factor H from connecting with the sugar and in turn, disabling the complement regulation by which factor H deters a misdirected immune response.
The tea says that in turn the resulting immune system response to chemicals released by the lysing of killed cells could be responsible for the organ damage and failures seen in severe cases of COVID-19.
Significantly, the study team found by blocking another complement protein, known as factor D, which works immediately upstream in the pathway from factor H, they were able to stop the destructive chain of events triggered by SARS-CoV-2.
Dr Brodsky added, “When we added a small molecule that inhibits the function of factor D, the APC wasn’t activated by the virus spike proteins. We believe that when the SARS-CoV-2 spike proteins bind to heparan sulfate, it triggers an increase in the complement-mediated killing of normal cells because factor H, a key regulator of the APC, can’t do its job.”
As an illustration, Dr Brodsky says think of the APC like a car in motion. He explains, “If the brakes are disabled, the gas pedal can be floored without restraint, very likely leading to a crash and destruction. The viral spike proteins disable the biological brakes, factor H, enabling the gas pedal, factor D, to accelerate the immune system and cause cell, tissue and organ devastation. Inhibit factor D, and the brakes can be reapplied and the immune system reset.”
Dr Brodsky adds that cell death and organ damage from a misdirected APC associated with factor H suppression is already known to occur in several complement-related human diseases, including age-related macular degeneration, a leading cause of vision loss for people age 50 and older; and atypical hemolytic uremic syndrome (aHUS), a rare disease that causes clots to block blood flow to the kidneys.
The study team hopes that their work will encourage more study into the potential use against COVID-19 of complement-inhibiting drugs already in the pipeline for other diseases.
Dr Brodsky added, “There are a number of these drugs that will be FDA-approved and in clinical practice within the next two years,” “Perhaps one or more of these could be teamed with vaccines to help control the spread of COVID-19 and avoid future viral pandemics.”
In conclusion, the study team said that SARS-CoV-2 spike proteins convert non-activator surfaces to activator surfaces by preventing the inactivation of the cell surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.
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