A Present Update of Camostate and the Role in SARS-CoV-2 Infection

Abstract

SARS-CoV-2 has triggered a pandemic of "coronavirus disease-2019" (Covid-19). Viral cell entry of coronaviruses relies on the binding of viral spike protein (S protein) to cellular receptors and S type of protein processing by the host cell proteases. It is known that SARS-CoV-2 uses the human receptor ACE2 for cell entry and the serine protease TMPRSS2 for "priming" of the S protein. Camostate has antiviral properties against coronaviruses. The effects are due to inhibition of the endogenous protease TMPRSS2, which the SARS-CoV-2 virus requires for the host cell entry (as well as exit). Camostate is a serine protease inhibitor. Camostate, which is already in clinical use, reduces cell infection. So far, this has been shown exclusively in cell lines or cell cultures, which do not reflect the complexity of the three-dimensional alveolar lung cell association with type I, type II cells, endothelial cells and alveolar macrophages.It is well known, that Camostate blocks TMPRSS2 and related proteases [1-36]. For SARS-CoV-2 to enter lung cells, the virus must be activated by the cellular protease TMPRSS2. Camostateis used in Japan to treat inflammation of the pancreas, blocks the protease TMPRSS2 and thereby inhibit SARS-CoV-2[1-18,20-29,31-35]. However, it was unclear whether the camostate degradation product GBPA also inhibits the virus and whether the virus can use related proteases for infection in addition to TMPRSS2, which may not be inhibited by camostate[18,20,29]. These proteases are available to the virus for replication in the upper respiratory tract and are inhibited by camostate[1-36]. It is therefore not possible for SARS-CoV-2 to evade the antiviral effect of Camostate by switching to related proteases instead of TMPRSS2. In further studies, the researchers were able to show that in addition to Camostate, the primary Camostate metabolite GBPA also inhibits the protease TMPRSS2, thereby blocking SARS-CoV-2 infection. Camostate is converted to GBPA in the body within a very short time.GBPA can exert an antiviral effect in patients. A higher dosage of Camostate to effectively treat COVID-19 than to treat pancreatic inflammation may be required [33,36]. Inhibition of SARS-CoV-2 by Camostate had initially been shown only in the lung cell line Calu-3[6]. The involvement of researchers from Hannover, Germany, made it possible to analyze the antiviral effect of Camostatein real lung tissue as well [6]. Camostate and GBPA inhibit SARS-CoV-2 infection of lung tissue [15]. The camostatemesilate-containing drug Foipan® has been available on the Japanese market since 1986 [1-36]. It is used to treat chronic inflammation of the pancreas and postoperative reflux esophagitis [33,36]. According to the product information, the substance has an inhibitory effect on several enzymes and intervenes in various systems in the body. Among other things, an inhibitory effect on trypsin and normalization of amylase levels are mentioned [33,36]. However, the reason why this substance suddenly becomes interesting in the corona crisis is different [24,26,30].