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Epidemiology and Pathogenesis of COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Sidrah Tariq Khan, Sagheer Ahmed
Drugs that have the ability to block the interaction between viral proteins and humanAce-2 receptors may result in areduction in viral load in infectedpatients and prove to be beneficial in treating the disease. Japan has approved the use of the antiviral drug Camostat mesylate, which is responsible for inhibiting serine protease enzymes such as TMPRSS2, which results in a reduction in viral entry into the host cell and also prevent the patient from reaching severe disease. Unfortunately, at present there is not enough clinical data to support the use of this drug in COVID-19 patients. In patients with milder disease, Umifenovir has been shown to be much more effective than ritonavir. However, the drug has not shown much promise when it comes to treating more severe COVID-19 cases. Previously, antimalarial drugs Chloroquine and hydroxychloroquine (HCQ) were being used to treat COVID-19 due to their ability to block viral entry via multiple mechanisms such as raising the endosomal PH making it more acidic and inhibition of receptor glycosylation thereby interfering with membrane fusion. However, due to their debilitating adverse effects, especially those related to the cardiovascular systems, the FDA has now unauthorized the use of these drugs in emergency cases.
Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
TMPRSS2: One of the best studied host proteases involved in RNA virus infection is the Type II transmembrane serine protease (TMPRSS2). This trypsin-like enzyme expressed on plasma membranes, functions by cleaving the intracellular domains of host receptors and is critical for SARS-CoV-2 infections [65]. Later, TMPRSS2 was identified as a therapeutic target for coronavirus and influenza virus infections [66]. TMPRSS2 was identified to be associated with SARS-CoV infected primate airways and its expression is increased after viral infection [67, 68]. The enzymatic cleavage of ACE2 by TMPRSS2 is critical for viral internalization. Such a cleavage of the ACE2 ectodomain facilitates the intracellular uptake of SARS-CoV-2. Furthermore, TMPRSS2 antagonizes ADAM17, an ecto-domain sheddase (discussed below), by preventing the ectodomain shedding of ACE2. In fact, camostat, the inhibitor of TMPRSS2, is known to inhibit replication of influenza virus in vitro [69] and was one of the first drugs discovered to have inhibitory effects against SARS-CoV-2. Recently, molecular modeling and crystallography showed camostat to bind directly to TMPRSS2. Besides camostat, nafamostat is another potential TMPRSS2 inhibitor and it has been shown in cell culture studies to block SARS-CoV-2 infection [70]. TMPRSS2 is also known to cleave the SARS-CoV-2 S protein directly, thus affecting the free/unbound virus. This cleavage by TMPRSS2 gives the virus two advantages: first it allows better fusion with host cell membranes, and second, better immune evasion by host immunoglobulins [71]. Therefore, TMPRSS2 involvement in SARS-CoV-2 pathogenesis is two-fold. Inhibitors against TMPRSS2 should both block viral binding/entry as well as improve humoral responses against the virus.
Drugs repurposing for SARS-CoV-2: new insight of COVID-19 druggability
Published in Expert Review of Anti-infective Therapy, 2022
Sujit Kumar Debnath, Monalisha Debnath, Rohit Srivastava, Abdelwahab Omri
The host cell proteases proteins (transmembrane protease serine 2-TMPRSS2, cathepsin L, furin, and calpain) help infuse the viral membrane. TMPRSS2 triggers the virus internalization by the cleavage of the viral hemagglutinin [16]. Hence, host cell protease inhibitors can be an alternative approach to restrict viral entry. Camostat mesylate is a TMPRSS2 inhibitor, primarily used to treat postoperative esophagitis and chronic pancreatitis. A randomized, placebo-controlled, double-blind multicentric trial was conducted with camostat mesylate on 137 patients infected with SARS-CoV-2 [39]. This drug successfully reduced the viral load by blocking the viral replication. Cathepsin L (CTSL) is another lysosomal cysteine protease hypothesized as the target to prevent viral fusion into the host cell membrane [40]. CTSL cleaves the S1 subunit spike glycoprotein of CoV. This cleavage helps CoV to invade human host cells. After endosomal membrane fusion, the viral RNAs are released for replication. Aloxistatin is a cysteine protease inhibitor for CTSL. This drug showed inhibitory activity in the mouse model infected with hepatitis virus by irreversibly binding with the active site of cysteine. This drug also reduced SARS-CoV-2 entry by 92.3% [16]. Structural elucidation suggested an interaction between the active site of SARS-CoV-2 main protease (Mpro) with the permeable membrane resulting in developing nonstructural protein (NSP). This drug also binds with papain-like proteases with less specificity. This evidence suggested that aloxistatin is a more potent drug for COVID-19.
Drug repurposing strategies and key challenges for COVID-19 management
Published in Journal of Drug Targeting, 2022
Shubham Mule, Ajit Singh, Khaled Greish, Amirhossein Sahebkar, Prashant Kesharwani, Rahul Shukla
TMPRSS2 dependant spike protein cleavage is the fundamental step in the entry of viruses into human cells. Vero E6 cells, due to their property of TMPRSS2 overexpression, are being widely utilised in research against COVID [47]. In humans, TMPRSS2 is found abundantly in cells of the lungs [48] which explains the vulnerability of lungs to infection. Therefore, inhibition of TMPRSS2 may prove to be a promising treatment approach to control the COVID infection [40,49]. The protease inhibitors like camostat, nafamostat and AEBSF are expected to exhibit TMPRSS2 inhibitory action [50]; however, only camostat has shown promising in vitro results. Bromhexine, a well-known mucolytic agent is known to possess TMPRSS2 inhibitory action as well, hence its repositioning in SARS-CoV2 therapy is under consideration [51]. A novel approach under consideration is the transcriptional inhibition of TMPRSS 2 using androgen and oestrogen-related drugs [52]. These compounds are known to downregulate TMPRSS2 in lungs, hence oestrogen pathway activation and androgen pathway inhibition can prove to be a potential target of therapeutic intervention against SARS-CoV2 [53].
The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19
Published in Expert Opinion on Drug Discovery, 2022
Christiana Mantzourani, Sofia Vasilakaki, Velisaria-Eleni Gerogianni, George Kokotos
Gabexate mesilate (8, Figure 3) is a TMPRSS2 inhibitor, which has been approved for use in Italy and Japan for the treatment of pancreatitis and disseminated intravascular coagulation [91]. It has been established that gabexate mesilate can inhibit influenza virus A and B in vitro in MDCK and human tracheal epithelial cells [57,76], and in vivo in a murine model [92]. This inhibitor is similar to camostat and nafamostat in structure, but less effective in most cases. Recently, in an enzymatic TMPRSS2 assay, Shrimp et al. reported that gabexate mesilate inhibited TMPRSS2 with an IC50 value of 130 nM and was the least potent compound compared to nafamostat mesilate (IC50 0.27 nM), camostat mesilate (IC50 6.2 nM) and FOY-251 (IC50 33.3 nM), while bromhexine hydrochloride showed no inhibition of TMPRSS2 [93].