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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.
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.
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
Camostat mesilate (4) was first synthesized by Ono Pharmaceutical 45 years ago [47,48]. It is currently an approved drug in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis, under the trade name FOIPAN® [49]. Supporting this application, it has been demonstrated that camostat mesilate administration prevented the progression of pancreatic fibrosis in rats [50]. Furthermore, when given to hypertensive rats, camostat mesilate causes reduction of blood pressure, and overall improvement of kidney function, potentially by inhibiting prostasin, a protein implicated in epithelial sodium channel regulation [51]. When applied to airway mucous membranes, camostat inhibits the airway epithelial sodium channel (ENaC) function in Guinea pig trachea and enhances the mucociliary clearance in sheep bronchi [52]. In addition, it reduces sodium transport in the airway of humans with cystic fibrosis [53]. Intriguingly, an association between the use of camostat mesilate and reduction of hematuria and/or proteinuria in children has been observed [54]. Finally, in a study using genetically obese and diabetic rats, administration of camostat mesilate was able to reverse hyperglycemia and obesity and improve insulin resistance [55].
Possible therapeutic agents for COVID-19: a comprehensive review
Published in Expert Review of Anti-infective Therapy, 2020
Khaled Mosaad Elhusseiny, Fatma Abd-Elshahed Abd-Elhay, Mohamed Gomaa Kamel
Camostat mesilate, or camostat mesylate, is a synthetic serine protease inhibitor developed for oral squamous cell carcinoma, and dystrophic epidermolysis. In a trial, 95 patients received 200 mg camostat mesilate three times daily for 2 weeks and showed only mild, but no severe side effects in patients with dyspepsia associated with nonalcoholic mild pancreatic disease [37], demonstrating that camostat mesilate is a well-tolerated intervention. In Japan, nafamostat mesilate, as a clinically confirmed and synthetic serine protease inhibitor, was approved for the treatment of acute pancreatitis, disseminated intravascular coagulation, and for anticoagulation in the extracorporeal circulation [3839–40].