Epidemiology and Pathogenesis of COVID-19
Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga in The Covid-19 Pandemic, 2023
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
Debmalya Barh, Kenneth Lundstrom in COVID-19, 2022
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.
An overview on the use of antivirals for the treatment of patients with COVID19 disease
Published in Expert Opinion on Investigational Drugs, 2021
Maricar Malinis, Dayna McManus, Matthew Davis, Jeffrey Topal
Camostat mesylate is a serine protease inhibitor approved for the treatment of chronic pancreatitis and post-operative esophagitis in Japan. Camostat can inhibit viral replication of SARS-CoV and MERS-CoV in tissue cultures through inhibition of TMPRSS2, which is responsible for S protein priming (Figure 1)[5]. In mice model, it was protective against mortality following a lethal dose of SARS-CoV [110]. Due to similar viral mechanisms, camostat may be a potential anti-viral drug against SARS-CoV-2. Currently, there are eight ongoing clinical trials of camostat for COVID-19 worldwide registered in Clinicaltrials.gov [111]. Camostat is an oral drug with minimal side effects [gastrointestinal (1%) and skin disorders (0.5%)] and no serious adverse reactions in a post-marketing study in Japan. Hence, the drug is an attractive potential, safe option for mild disease that can be used in non-hospitalized COVID-19 patients. However, this remains to be determined by ongoing trials.
Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature
Published in Expert Opinion on Therapeutic Patents, 2020
Alexandre Murza, Sébastien P. Dion, Pierre-Luc Boudreault, Antoine Désilets, Richard Leduc, Éric Marsault
Since the emergence of the COVID-19 pandemic, TMPRSS2 has become a center of attention of the scientific community. A recent pre-print article focuses on proteolytic inhibition of several known serine protease inhibitors to find a treatment [72]. Camostat, BHH (bromhexine), A1AT (alpha 1-antitrypsin protein), and AEBSF 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride Figure 3 inhibitory capacities were tested at concentrations of 100 nM – 100 µM on TMPRSS2-transfected cells using a fluorogenic substrate. Whereas BHH, A1AT, and AEBSF inhibited TMPRSS2-dependent activity in a dose-dependent manner with a maximum effect reached at 1 µM, camostat demonstrated full efficacy even at 100 nM. The use of camostat, a compound clinically approved in Japan to treat pancreatitis, was previously patented for the treatment of respiratory diseases, particularly cystic fibrosis, and chronic obstructive pulmonary disease (US20120208882) [73]. It was shown to block MERS-CoV entry into a well-differentiated lung-derived cell line [39]. It was also previously considered as a drug candidate to prevent TMPRSS2-dependent infection by SARS-CoV [74]. Camostat also inhibits recombinant human matriptase with nM potency and, to a lesser extent, prostasin [63]. The analogous nafamostat Figure 3 is a more potent inhibitor of matriptase and was also recently proposed as a potential avenue for the treatment of COVID-19 [75–78].
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.
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