Furin & Cathepsin L: New targets
for Covid-19 drug screening

Coronavirus disease 2019 (COVID-19) has become a huge and ongoing global health crisis, affecting the millions of people worldwide who have been infected and shutting down global economies. While vaccines are now being rolled out, treatments for patients who are suffering from COVID-19 are still lacking. Key targets exist which scientists are focusing on as potential anti-virals which would be effective against this potentially deadly disease. Read on to understand how these targets function and how blocking them could help treat COVID-19.

The rapid spread of the new coronavirus SARS-CoV-2 has resulted in a global pandemic of coronavirus disease (COVID-19) sadly resulting in millions of deaths and many more patients ill. The pandemic has shutdown economies all over the world.

While development of effective vaccines proceeded quickly and allowed the development of worldwide vaccination programs, there are still no effective therapies available to treat COVID patients with severe and life-threatening symptoms. Recent findings indicate the disease is hard to manage therapeutically and standard antivirals seem to be ineffective. Development of anti-viral drugs that inhibit or at least reduce viral spread and attenuate pathogenesis would be highly valuable in fighting the COVID-19 pandemic.

Currently, scientists worldwide are studying the infection process of SARS-CoV-2, searching for effective therapeutic solutions to prevent and cure the disease. One of most important targets in COVID-19 research is the Spike (S) Protein on the surface of the viral envelope that interacts with the ACE2 receptor on the surface of human cells. This protein mediates either fusion of the virus membrane with the host cell membrane (TMPRSS2 activated mediation) or endocytosis of the virus particle (Cathepsin-activated mediation) and its entry into the cell. The S Protein is important in both mechanism studies and the development of vaccines and therapeutics such as antibodies and chemical drug compounds.

By both routes, the S Protein plays a vital role in the process of SARS-CoV-2 infection. Recent research has found that both prior to and after attachment, the S Protein requires activation by cellular proteases (such as the serine protease TMPRSS2) to trigger viral entry into the target cell. A new approach to impede S Protein activation is being considered.

Another protease essential for priming the S Protein is Furin protease. It seems a furin-like cleavage site (FCS) in the S Protein, absent in other lineage B βCoVs (such as SARS-CoV), is responsible for the high infectivity and transmissibility of COVID-19. The pathogenicity of some coronaviruses strongly depends on the furin-like cleavage of the S Protein, which seems to worsen the symptoms of viral bronchitis, as well as increase viral pathogenicity.

A further host protease required for activation of the S Protein is Cathepsin L which also facilitates SARS-CoV-2 entry into target cells through an alternative route. This route enables virus uptake via endosomes by receptor-mediated endocytosis. The S Protein is then processed/activated by the lysosomal Cathepsin L in the late endosomes (endo-lysosomes) following endocytosis of the virus.

Inhibition of the Furin protease and Cathepsin L might therefore be an efficient way to attenuate the infection process and reduce the spread and severity of COVID-19. Specific Furin and Cathepsin L inhibitors which block proteolytic activation of the S Protein, and thus SARS-CoV-2 virus entry and replication, are potential antiviral agents to counteract SARS-CoV-2 infection and pathogenesis.

In addition to our assays for studying binding of SARS-CoV-2 to the ACE2 receptor and screening for respective inhibitors/drugs (see below), we offer the Furin Activity Assay Kit & Furin Inhibitor Screening Kit as well as Cathepsin L Activity Assay Kit & Cathepsin L Inhibitor Screening Kit as tools to develop new targeted therapeutics for Covid-19. In addition, a broad range of other Cathepsin Assays, Cathepsin Inhibitors as well as recombinant Cathepsins, Cathepsin antibodies & ELISAs also useful to study SARS-CoV infections (e.g. Cathepsin B) are available at PromoCell. We also supply a choice of Biochemicals with known inhibitory effects on SARS-CoVs as well as a range of high-quality Antibodies specifically directed against particular components of SARS-CoV and the ACE2 receptor.

Spike (S) Protein priming is essential for entry of SARS-CoV-2 and relies upon the cell surface protease TMPRSS2 (transmembrane protease serine 2) and the protease Furin. The S1/S2 activation sequence of the SARS-CoV-2 S Protein requires cleavage by the cellular protease Furin to enable infection of lung cells. The activation sequence is also important for the fusion of infected cells with non-infected cells, which might allow the virus to spread in the body without leaving the host cell. The furin-cleaved S1 fragment of the Spike (S) Protein binds directly to cell surface NRP1 (Neuropilin-1) which significantly potentiates SARS-CoV-2 infectivity. Neuropilin-1 (NRP1) has been proposed as a novel SARS-CoV-2 host cell entry mediator implicated in COVID-19.
Figure 2:
After the SARS-CoV-2 virion attaches to the host surface receptor ACE2, Spike (S) Protein activation/priming occurs by the host proteases TMPRSS2 and Furin (transmembrane) or Cathepsin L (endosomal) thus providing two independent entry pathways. The viral entry takes place either by receptor-mediated endocytosis (left) or by membrane fusion (right). In both routes, the viral RNA is released, and the late stage of the life cycle takes place by RNA replication. Blocking these pathways is essential for preventing infection of the cell expressing both proteases.

Please note that our Spore-EX Disinfection Spray has been tested for its efficacy against coronavirus (validated according to EN14476).

See also our wide range of products for Respiratory Research.

Note: All products are for research use only and not for in vitro-diagnostic or therapeutic purposes.

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Our portfolio for COVID-19 research includes a wide range of characterized primary cells, optimized cell culture growth medium for each cell type, a broad choice of cell-based and cell-free assays, cell stains, as well as numerous cytokines & growth factors, antibodies and ELISAs useful in respiratory research.

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