8.A.131.1.6
TMPRSS2 of 492 aas and one TMS near the N-terminus. It and kallikrein 3, KLK3 (TC# 8.A.131.1.5) can be used for molecular lymph-node staging in prostate cancer patients undergoing prostatectomy (Lunger et al. 2020). Camostat mesylate is a potent inhibitor of the human transmembrane protease, serine 2 (TMPRSS2) and is under investigation for its effectiveness in COVID-19 patients. Its active metabolite is 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). OATP2B1 is inhibited by GBPA with an IC50 of 11 muM (Weiss et al. 2021). Although nafamostat and camostat have been identified as TMPRSS2 inhibitors, severe side effects such as cerebral hemorrhage, anaphylactoid reaction, and cardiac arrest shock greatly hamper their clinical use. Flupirtine, a selective neuronal potassium channel opener, is a potential TMPRSS2 inhibitor (Chen et al. 2021). TMPRSS2 proteolytically activates the epithelial sodium channel (ENaC) (TC# 1.A.6) by cleaving the channel's gamma-subunit (Sure et al. 2022). Dual inhibition of vacuolar-ATPase and TMPRSS2 is required for complete blockade of SARS-CoV-2 entry into cells (Icho et al. 2022). This is because an essential step in the infection life cycle of SARS-CoV-2 is the proteolytic activation of the viral spike (S) protein, which enables membrane fusion and entry into the host cell. Two distinct classes of host proteases have been implicated in S protein activation: cell-surface serine proteases, such as the cell-surface transmembrane protease, serine 2 (TMPRSS2), and endosomal cathepsins, leading to entry through either the cell-surface route or the endosomal route, respectively (Icho et al. 2022). Potential TMPRSS2 inhibitors for COVID-19 treatments have been identified in chinese medicines (Yang et al. 2023). Angiotensin converting enzyme 2 (ACE-2), transmembrane serine protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells including astrocytes in the blood brain barrier (BBB) (Malik et al. 2023).