Friday Hope: Fostamatinib/R406 Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation

Given evidence that S Protein Immune Complexes Also Induce SPED, R406 May Be A Significant Therapeutic For COVID, Perhaps Moreso For Long COVID

To recap my most recent post, evidence has emerged supporting my hypothesis that not only the Spike Protein of SARS-CoV-2 induces SPED, but also its immune complexes.

All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets.

And the paper concludes:

Injury to the microvasculature by immune complexes with complement activation is the key central event that results in breakdown of the blood–brain barrier, microthromboses, perivascular inflammation and neuronal injury. We postulate that these events are central to the development of the neurological manifestations seen in acute COVID-19 and possibly in long-COVID. Importantly, these studies suggest that therapeutic approaches targeted against the development of immune complexes should be considered.

Neurovascular injury with complement activation and inflammation in COVID-19
https://academic.oup.com/brain/article/145/7/2555/6621999

If it is not possible to reduce the presence of immune complexes after exposure to the Spike Protein of SARS-CoV-2, it appears to be possible to reduce the inflammation caused by the immune complexes. Reducing this inflammation may not only help those with acute COVID, but I also believe it may be extremely beneficial to those suffering from Long COVID. We need trials to determine the extant of this efficacy, if it is indeed true.

Therefore, I am in complete agreement with the study’s conclusion, and so I began a search for existing pharmaceuticals which could be repurposed to achieve the goal of reducing immune complexes in the presence of the Spike Protein. Though I did not find one that reduces the immune complexes themselves, I found one that is extremely promising, as it reduces the inflammation caused by immune complexes, which is the present danger caused by them. That pharmaceutical is Fostamatinib/R406.

The main effect of Fostamatinib is:

Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.

And, what I find particularly interesting:

Moreover, they showed that R406 inhibited cytokine and matrix metalloproteinase production from TNF-induced RA fibroblast-like synoviocytes.

The conclusion shows how the pharmaceutical does not appear to interfere with the innate immune response, which I believe is important.

In summary, we have developed R406 as a potent Syk kinase inhibitor using biology-directed drug discovery. We have shown that R406 has potential for broad anti-inflammatory properties because it inhibits several critical nodes of the inflammatory cascade without interfering markedly with the innate immune response or hemostasis. Our results with R406 support Syk inhibition as a novel therapeutic approach for inflammatory arthritis and other immune-mediated inflammatory diseases.

R406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation
https://www.researchgate.net/profile/Stipo-Jurcevic/publication/6843020_R406_an_Orally_Available_Spleen_Tyrosine_Kinase_Inhibitor_Blocks_Fc_Receptor_Signaling_and_Reduces_Immune_Complex-Mediated_Inflammation/links/569f812908ae2c638eb7a785/R406-an-Orally-Available-Spleen-Tyrosine-Kinase-Inhibitor-Blocks-Fc-Receptor-Signaling-and-Reduces-Immune-Complex-Mediated-Inflammation.pdf

Very interestingly, a computational screening from July of this year identified Fostamatinib as a potential therapeutic for COVID (initial graphic). It was identified as consensus scoring highest for candidate drugs for COVID spreader proteins, and it is also used for Thrombocytopenia.

In this computational study, we have analyzed the Human-nCoV PPIN and attempted to identify the candidate drugs for the level-1 and level-2 spreader proteins. Our study identifies Fostamatinib/R406, an FDA approved drug, as the most promising drug with the best chances to target the COVID-19 spreader proteins. The work relies on the hypothesis that SARS-CoV2/nCoV has ~89% genetic resemblance with SARS-CoV. Based on this, Human-nCoV PPIN has been developed, and its spreader nodes have been identified using the SIS model and fuzzy thresholding. Furthermore, a consensus strategy by a two-way analysis has been utilized to analyze drugs based on the overlap of spreader proteins and drug-protein targets. The consensus scores for Fostamatinib/R406 are highest in analysing the candidate drugs for COVID-19 spreader proteins. Besides, Fostamatinib/R406 also generates satisfactory results in molecular docking with the available COVID-19 protein structures. It also targets CAYP34A, a common target for almost all the FDA approved drugs for COVID-19. Moreover, recent studies also suggest that it is used for thrombocytopenia which is also associated with severe coronavirus disease 2019 (COVID-19) infections.

Drug repurposing for COVID-19 using computational screening: Is Fostamatinib/R406 a potential candidate?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390099/

Given that Fostamatinib has been computationally identified as a potential therapeutic for COVID, I believe it should be trialed immediately for COVID, Long COVID and SPED. I also believe my findings that the Spike’s immune complexes also induce SPED provide additional impetus to begin trials immediately.