Also known as PACE (Paired basic Amino acid Cleaving Enzyme) --> FUR, PACE, PCSK3, SPC1
© 2021 PFPC
A recent article in "Nature" once again highlighted the importance of the furin cleavage site, a much-studied region of the spike protein. It is believed that the furin cleavage site might be the source of the increased infectivity of the Delta variant (Callaway, 2021).
Interestingly, just about five weeks earlier a new US patent was granted to Applied Biology, Inc. involving the use of anti-thyroid agents in the treatment of respiratory viral infections, "specifically SARS-CoV-2 infections". The invention includes a method to inhibit furin expression by inhibition of T3, the thyroid hormone (Goren et al., 2021).
The researchers wrote:
"...SARS-CoV-2 spike protein has been revealed to contain a furin cleavage sequence... As such, viral spike protein priming may be mediated through furin protease in addition to TMPRSS2. Furin expression has been demonstrated to be up-regulated by thyroid hormone T3 and its expression was cooperative with transforming growth factor beta or TGF-.beta..."(Goren et al., 2021)
Fluoride has also long been known to interfere with TGF-β, a pathway critical to furin expression (Jiang et al., 2021; Yu et al., 2018; Zhang et al., 2019; Kido et al., 2017).
Bone studies have shown that fluoride effects on TGF-β are biphasic. Low doses have the opposite effects as high doses (stimulating at low doses - inhibiting at high doses, or vice-versa) (i.e. Jiang et al. 2021). This, of course, is in line with fluoride's established role as a universal G protein activator [G(s), G(i), Gq/11, G12/13].
Furin expression is upregulated by T3 (Chen et al., 2008), and mediated by Gq/11 proteins.
Fluoride's pharmacological efficacy as an anti-thyroid agent is well established (PFPC, 2020).
- Callaway Ewen - "The mutation that helps Delta spread like wildfire"
A key amino-acid change might underlie the coronavirus variant’s ferocious infectivity.
Nature, August 20, 2021
Goren et al. "Systems, methods, and kits for diagnostics and treatment of viral respiratory infection" US Patent 11,058,647 (July 3, 2021)
https://patft.uspto.gov/netacgi/nph-Par ... 11,058,647
PFPC - 40 Papers - Fluoride as Anti-Thyroid Medication
Liu Y, Liu J, Johnson BA, Xia H, Ku Z, Schindewolf C, Widen SG, An Z, Weaver SC, Menachery VD, Xie X, Shi PY - "Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant" bioRxiv [Preprint]. 2021 Sep 5:2021.08.12.456173. doi: 10.1101/2021.08.12.456173. PMID: 34462752; PMCID: PMC8404900
"Spike mutations that potentially affect furin cleavage efficiency must be closely monitored for future variant surveillance."
Li W - "Delving deep into the structural aspects of a furin cleavage site inserted into the spike protein of SARS-CoV-2: A structural biophysical perspective" Biophys Chem 264:106420 (2020)
Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E - "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade" Antiviral Research 176:104742 (2020) doi:10.1016/j.antiviral.2020.104742
Jiang N, Xu W, Zhang Z, Jin H, Yang Y, Zhang J, Xu H - "Role of TGF-β1 in Fluoride-Treated Osteoblasts at Different Stages" Biol Trace Elem Res. 2021 May 24. doi: 10.1007/s12011-021-02686-2. Epub ahead of print. PMID: 34031801
Yu H, Jiang N, Yu X, Zhao Z, Zhang X, Xu H - "The role of TGFβ receptor 1-smad3 signaling in regulating the osteoclastic mode affected by fluoride" Toxicology. 393:73-82 (2018)
Zhang J, Jiang N, Yu H, Yu X, Guo F, Zhao Z, Xu H - "Requirement of TGFβ Signaling for Effect of Fluoride on Osteoblastic Differentiation" Biol Trace Elem Res 187(2):492-498 (2019) doi: 10.1007/s12011-018-1387-x. Epub 2018 May 16. PMID: 29770951
Kido T, Tsunoda M, Sugaya C, Hano H, Yanagisawa H - "Fluoride potentiates tubulointerstitial nephropathy caused by unilateral ureteral obstruction" Toxicology 392:106-118 (2017) doi: 10.1016/j.tox.2017.10.003. Epub 2017 Oct 9. PMID: 29024711
Suzuki M, Shin M, Simmer JP, Bartlett JD - "Fluoride affects enamel protein content via TGF-β1-mediated KLK4 inhibition" J Dent Res 93(10):1022-7 (2014) doi: 10.1177/0022034514545629. Epub 2014 Jul 29. PMID: 25074495; PMCID: PMC4212320
Hasan MK, Alam S, Mirkovic J, Hossain MF - "Screening of Human Proteins for Fluoride and Aluminum Binding" Bioinformation 14(2):68-74 (2018)
Furin expression is mediated by the Gq/11 pathway.
Uchiyama K, Saito M, Sasaki M, Obara Y, Higashiyama S, Nakahata N - "Thromboxane A2 receptor-mediated epidermal growth factor receptor transactivation: involvement of PKC-delta and PKC-epsilon in the shedding of epidermal growth factor receptor ligands" Eur J Pharm Sci 38(5):504-11 (2009)
"These results suggest that TP-mediated EGFR transactivation is partially caused by shedding of HB-EGF, which involves furin and ADAM via novel types of PKCs (PKC-delta and PKC-epsilon) through G alpha(q/11) proteins in an extracellular Ca(2+)-dependent manner."
Grewal JS, Mukhin YV, Garnovskaya MN, Raymond JR, Greene EL - "Serotonin 5-HT2A receptor induces TGF-beta1 expression in mesangial cells via ERK: proliferative and fibrotic signals" Am J Physiol 276(6):F922-30 (1999)
Matsuzaki S, Ishizuka T, Yamada H, Kamide Y, Hisada T, Ichimonji I, Aoki H, Yatomi M, Komachi M, Tsurumaki H, Ono A, Koga Y, Dobashi K, Mogi C, Sato K, Tomura H, Mori M, Okajima F - "Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells" Biochem Biophys Res Commun 413(4):499-503 (2011)
Ventura E, Weller M, Burghardt I - "Cutting Edge: ERK1 Mediates the Autocrine Positive Feedback Loop of TGF-β and Furin in Glioma-Initiating Cells" J Immunol 198(12):4569-4574 (2017)
Chen RN, Huang YH, Lin YC, Yeh CT, Liang Y, Chen SL, Lin KH - "Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines" Endocrinology 149(8):3817-31 (2008)"The present results indicate that T3 up-regulates furin gene expression in HepG2-TRα1 and -TRβ1 cells. This T3-mediated induction in TRα1 and β1 overexpressing cells is observed at both mRNA and protein levels. Similar findings were obtained in Tx rats after administration of T3. The results most likely indicate that T3 cooperates with TGF-β signaling and its components, Smad3/4, in controlling furin expression." (Chen et al., 2008)
Regarding the use T3 in the treatment of COVID-19, we are waiting for the results of a US clinical trial evaluating the use of instilled T3 in the treatment of ARDS (Flory et al., 2021; https://clinicaltrials.gov/ct2/show/NCT04115514). Patent applications have been filed here as well.
Flory CM, Norris BJ, Larson NA, Coicou LG, Koniar BL, Mysz MA, Rich TP, Ingbar DH, Schumacher RJ - "A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS" J Pharmacol Exp Ther 376(1):74-83 (2021)