Recent studies identify that coronavirus infect the cell by the use of envelope-anchored spike protein that binds to the cell membrane and the binding site is activated by host cell enzyme furin. Furin is found in several human tissues in the body.
Is there any drug available to block these receptors?
Ref: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008392
https://www.nature.com/articles/s41598-018-34171-7
https://www.nature.com/articles/d41586-020-00660-x
Many inhibitors of furin have been described. Some of the literature can be found here:
https://brenda-enzymes.org/enzyme.php?ecno=3.4.21.75#IC50%20VALUE%20[mM]
Blocking the activity of furin would probably have unwanted side effects due to its important functions:
https://en.wikipedia.org/wiki/Furin
A virus-targeted strategy, such as a vaccine or an inhibitor of the function of a viral protein, might offer more hope of avoiding such side effects.
Thanks so much for your insights Adam B Shapiro . I appreciate you taking the time to share these very useful resources. Although, the development of vaccine looks like a better strategy. Several news sites reported that herd immunity is the UK's strategy for coronavirus. But I'm afraid that new strains might emerge in a short time needing repeated vaccines. I guess viral protein inhibition is the way.
Some of studies were used the furin inhibtor like (piptidylchloromethylketone)
According to a report of the 20 Marzo 2020, by the Italian National Institute of Health, on 3199 patients who have died from coronavirus, the median age of death is 78.5 (median 80, range 31-103, IQR 73 -85), while the median age of the people who got infected is 63. As of March 20, among the coronavirus victims only 36 people were younger than age 50 and only 29.4% were women. Considering the age of the infected-died people they can be subdivided in four groups: a) low risk (1.1%) with age between 30 and 49 years; b) low-moderate risk (2.9%) from 50 to 59 years; c) moderate risk (10.3%) those aged 60-69 inclusive, and d) high risk (85.7%) having age > 70 years. Always according to this study, most of the people who have died suffered from previous illnesses before contracting the coronavirus. Based on a sample of 481 out of 3199 patients dying in-hospital hospital (15.0% of the sample), the institute found that almost half of the victims had three or more illnesses, a quarter had either two or one prior medical condition. Mean number of diseases was 2.7 (median 2, SD 1.6). Overall, 1.2% of the sample presented with a no comorbidities, 23.5% with a single comorbidity, 26.6% with 2, and 48.6% with 3 or more. Most common comorbidities observed in SARS-CoV-2 positive deceased patients are that way distributed: high blood pressure (73.8%), diabetes (33.9%), ischemic heart disease (33%), atrial fibrillation (22.0%), chronic renal failure (20.2%), active cancer in the past 5 years (19.5%), COPD (13.7%), Dementia & Stroke (11.9%, and 11.2% respectively).
Retracing pathogenetic knowledge of the SARS-ConV-2, the factor that allows viral entry is linked to enzymes, proprotein convertases (PCs), located on membrane surface that allows to modify the molecular spike on the envelope of the virus. PCs and particularly the furin, that biologically are responsible for the activation of a wide variety of precursor proteins, such as growth factors, hormones, receptors and adhesion molecules, but also have the potential to cleave specifically viral envelope glycoproteins, enhancing viral fusion with host cell membranes. Spike S1/S2 protein of SARS-ConV-2 is cleaved by furin generating the S1 and S2 subunits. The SARS-CoV-2 S1-protein contains a conserved Receptor Binding Domain (RBD), which recognises the angiotensin-converting enzyme 2 (ACE2). These variation, around the viral envelope glycoprotein cleavage site, plays a role in cellular tropism and pathogenesis, such as showed during Infectious Bronchitis Virus (IBV) in which, S-protein results in higher pathogenicity, pronounced neural symptoms and neurotropism in infected chickens. Furin is extremely increased in elder subjects, and is also termed a "master switch of tumor growth and progression", and its aberrant expression or activation can promote the formation and progression of various malignancies, and similar aberrant proteolitic activation is present in diabetes, chronic inflammation and neurological disease. In this last, furin is involved in NMDA-induced neuronal injury by acting upstream of calpain. During heart ischemic (MI) an up-regulation of furin and TGF-β1 occur, and in hypertension, furin gene may play a pivotal role in the renin-angiotensin system and maintaining the sodium-electrolyte balance, while in patients suffering from atrial fibrillation, furin is the major convertase responsible for the generation of Bone Morphogenetic Protein 10 (BMP10) that is estricted to the right atrium. All this nosological condition are superimposable with those that worsen SARS-ConV-2 infection.
Considering that, host cells infected by viruses provoke an interferon response to inhibit the enzymatic activity of furin-like enzymes, the use of inhibitors of furin-like enzymes may contribute to inhibiting virus propagation, using, to avoid sitemic effects of furin inhibitors, inhalation via, that exhibiting a slow dissociation rate from furin to allow sustained inhibition against SARS-CoV-2.
Please go through the article.
Article Effects of Human Anti-Spike Protein Receptor Binding Domain ...