What are Proprotein converases?

Proprotein covertases(PC) is made of 9 serine secretory proteases that regulate biological processes in both healthy and disease states. They are responsible for activating precursor proteins and most relevant cell surface glycoproteins of infectious viruses. 7 PCs are known to cleave precursor proteins at specific single or paired amino acids within a known motif. 

Because PCs processing cell surface proteins is vital to viral infections, furin is a target of interest for SARS-CoV-2 research. Furn has potential to cleave specifically viral envelope glycoproteins to enhance viral fusion with host cell membranes.

Coronavirus cleavage sites

For human infecting corona viruses HCoV-OC43, MERS-CoV, HKU1 the spike protein is cleaved at an S1/S2 cleavage site generating tht S1 and S2 subuinits and demonstrate the same motif(canonical (R/K)-(2X)n-(R/K)↓ motif). The variation around the viral envelope glycoprotein cleavage site plays a role in cellular tropism and pathogenesis. So the pathogenesis of some CoV are related to the presence of a furin-like cleavage site in the S-Protein sequence. Which means the presence or insertion of the cleavage site increases pathogenesis.

SARS-CoV-2 vs SARS-CoV Spike Cleavage & Function

SARS-CoV-2 has a trimeric s protein that is processed at the S1/S2 cleavage site by host cell proteases during infection. During Priming the S protein is cleaved into N Terminal S1 protein and conctage cell receptors and S2 C terminal membrane anchored protein that fuses and viral entry

Both SARS-CoV and SARS-CoV-2 has a RBD to ACE2. SARS-CoV02 S2 has a fusion peptide with an internal fusion peptide and 2 heptade repeat domains preceding the transmembrande domain. IFP are identical for both SARS for viral fusion peptides. Molecular mechanisms for cell entry not yet fully understood. FP and IFP probably participate in viral entry process. So S protein most likely is cleaved at both S1/S2 and S2’ cleavage sites for virus entry.  Processing at S2’ is expected to be a key event for activation of S-Protein. Proteases involved in the process has not yet ben conclusively identified.  They propose 1 or more furin-like enzyme would cleave the S2’ site. The first cleavage between RBD and FP(S1/S2 cleavage site has been extensively studied for many CoVs.  The processing site for S1/S2 exhibits different motifs amog coronaviruses with many diplaying cleavage after a basic residue so priming by different host cell proteases depends on the S1/S2 sequence cleavage site. S protein for sars is largely uncleaved after biosynthesis possibly due to lack of favourable furin like cleavage sites. Target cell’s proteases such as elastase, athepsin L or TMPRSS2

The new sars has a canonical furin-like cleavage site that’s cleaved during virus egress leading to a gain of function to the virus.

SARS-CoV-2 Spike Gain of Function Impact

This gain of function is comparable to HIV  which induces expression of protease active receptor 1 (PAR1) or guanylate binding proteins 2 and 5 (GBP2,5) restrict the traffic of furin to the trans Golgi network (PAR1) or to early Golgi compartments (GBP2,5) where the proprotein convertase remains inactive. Research in the inhibition of furin-like enzymes may contribute to inhibiting virus propagation