Thread by @JSheltzer

Our new preprint on #COVID19 with Stefan Pöhlmann, Markus Hoffman, and @joans is up. We show that proteases other than TMPRSS2 are capable of promoting SARS-CoV-2 uptake, but camostat (and its active metabolite) can still inhibit their activity.

biorxiv.org/content/10.110…

TMPRSS2 is commonly described as “necessary” for SARS-CoV-2 activation. Many papers look at the expression patterns of ACE2+/TMPRSS2+ double-positive cells, ostensibly to shed light on which cell types are vulnerable to coronavirus infections. But it isn’t that simple!

ACE2 is necessary for viral uptake. TMPRSS2 expression in an ACE2+ cell is sufficient for uptake. But that DOES NOT mean that TMPRSS2 is also necessary! Hoffman et al. show that other TMPRSS-family proteases - particularly TMPRSS13 - are fully capable of activating SARS-CoV-2:

.@joans and I looked at the expression of these TMPRSS genes in tissues targeted by SARS-CoV-2. In the respiratory epithelium, many other TMPRSS’s are expressed in TMPRSS2-negative cells. TMPRSS11D is high in basal cells, TMPRSS13 in the nose, and TMPRSS11E in ionocytes.

21% of ACE2+ cells co-express TMPRSS2. 24% of ACE2+ cells are TMPRSS2-negative but co-express a different TMPRSS capable of viral activation. This likely expands the number of cells and the range of cell types that can be infected by SARS-CoV-2.

Hoffman et al. go on to show that these other TMPRSS proteases can still be inhibited by camostat, a “TMPRSS2 inhibitor” in clinical trials for COVID19.

Additionally, one concern with camostat as a treatment is that it has a very short half-life in vivo. Camostat is rapidly converted into GBPA, which is its major metabolite in the body.

Hoffman et al. found that FOY-251 (a methanesulfonate of GBPA) is about as effective at blocking SARS-CoV-2 pseudoparticle uptake as camostat, suggesting that camostat’s short half-life won’t necessarily be a problem for its use as a COVID19 therapy.

Take-aways from this work: sufficient ≠ necessary, COVID drugs, like cancer drugs, can have off-target activity against their target’s homologs, and a camostat metabolite remains able to block SARS-CoV-2 uptake.

(this is the paper I was talking about last week CC: @ImranSHaque @houndcl @cispt2)