Transmembrane protease serine 2: Difference between revisions
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== Expression == | == Expression == | ||
== | == Pharmacological therapeutic approaches == | ||
=== Inhibitors of TMPRSS2 === | |||
==== Nafamostat mesylate ==== | |||
Nafamostat mesylate (FUT-175; CAS number: 81525-10-2) is an artificial serine protease inhibitor clinically approved in Japan for the treatment of acute pancreatitis, intravascular coagulation dissemination, and extracorporeal circulation antioxidation. <ref>DOI 10.3390/cells9071652</ref> | |||
This drug is a competitive inhibitor of the binding active site, as well as Camostat. Both are reactive esters that form the same slowly-reversible phenylguanidino covalent complex with the catalytic serine (Ser441) residue of trypsin-like serine proteases. | |||
<ref>DOI 10.1101/2021.06.23.449282</ref> | |||
Nafamostat demonstrated enhanced potency over camostat with IC50 values of (1.7±0.2) and (17±4) nM, respectively. | |||
Although nafamostat potently neutralizes TMPRSS2 activity, it is non-selective and disables trypsin-like serine proteases involved in coagulation such as plasmin, FXa, and FXIIa, as well as other TTSPs through its generic arginine-like engagement with the S1 subsite. | |||
<ref>DOI 10.1101/2020.06.23.167544</ref><ref>DOI 10.1159/000215139</ref> | |||
Also it requires continuous intravenous infusion to approach therapeutic concentrations for COVID-19 owing to its short biological half-life of 8 minutes. | |||
[[Image:ACYL.jpg]] | |||
==== Camostat mesylate ==== | |||
==== Bromhexine ==== | |||
Repurposing of the mucolytic agent called bromhexine, a TMPRSS2 inhibitor, has been also proposed for COVID-19 therapy. | |||
<ref>DOI 10.1016/j.phrs.2020.104837</ref> | |||
==== Peptidomimetics ==== | |||
=== Transcriptional inhibition === | |||
Transcriptional inhibition of TMPRSS2 has been proposed as a new therapeutic option. Using computational and experimental methods, estrogen and androgen-related compounds such as genistein, estradiol, and enzatulamide (Figure 13B) have been shown to reduce TMPRSS2 expression in different cell lines.131 As TMPRSS2 expression in the human lungs seems to be modulated by estrogens and androgens, data suggest that the activation of estrogen pathways or inhibition of androgen pathways may be a new target for therapeutic clinical intervention for symptom amelioration in COVID-19 patients. | |||
10.20944/preprints202003.0360.v2 | |||
== Structural highlights == | == Structural highlights == | ||
