Ammonium Chloride as a Potential Candidate for the Treatment and Controlling of Covid-19

Coronaviruses, pathogens with a zoonotic potential, are positive sense single-stranded RNA viruses. SARS Coronavirus-2, the cause of Covid-19 infection, is from the betacoronavirinea subfamily, which has close genomic and proteomic similarity to SARS Coronavirus-1(1). Given the genomic proximity of these two viruses, studies on SARS Coronavirus-1 can be used to control or detect SARS Coronavirus-2. The cellular receptor of the virus is ACE-II, which virus binds to it through protein S (2). Protein S plays a major role in the pathogenesis of the virus by reducing the levels of the ACE-II receptor in the infected cells, disrupting the renin-angiotensin system as well as by affecting the tropism. Therefore, protein S is one of the important proteins in the pathogenesis of the virus and is a suitable target for treatment. (3,4) Protein S is a trimer spike on the virion surface, which consists of S1 and S2. The virus binds to the cell receptor via the surface globule (S1) and then enters the cell through receptor-mediated endocytosis. Cathepsin-L enzyme is an important cysteine ​​peptidase in the endosome. Within the endosome (lysosome) with the effect of Cathepsin-L enzyme, protein S is cleaved in S1/S2 junction. As a result, the fusion peptide at the S2 is exposed to the lysosomal membrane which is Followed by the virus nucleocapsid release to the cytosol and beginning of the viral replication. The higher the affinity of the protein S to the receptor, the higher the severity of the disease. (4,5) Important Notes: It appears at least some of the treatment strategies provided for Covid-19 are based on preventing the virus from being released from the endosome by inhibiting the cleavage of the S protein within the endosome. The Cathepsin-L enzyme, which is important in the process of virus replication, functions at pH = 4.7 and is inactivated at higher pH. (5,6) In SARS Coronavirus-1, inhibition of S1/ 2 cleavage, prevents the virus replication. (5,6)  S1/S2 cleavage can be prevented in several ways: 4.1. Lysosomotropic agents, which are weak bases, increase the lysosomes pH upon their entry into the lysosomes. As a result of increased pH, the Cathepsin-L enzyme is deactivated, preventing the fusion of the endosome membrane and the virus envelope which prevents the release of the virus nucleocapsid. These drugs include Chloroquine and Ammonium Chloride. In clinical trial, the efficacy of Chloroquine in the management of Covid-19 infection has been confirmed and this drug has been widely used to treat this infection in China and Iran. On the other hand, many experiments have confirmed the effectiveness of Ammonium Chloride. (7,8) 4.2. Cathepsin-L protease inhibitors can prevent the cleavage of S1/S2 by two manner: 4.2.1 . Competitive inhibitors such as peptides. Cathepsin-L can be inhibited by different types of peptides that have the enzyme cleavage site. (9) 4.2.2. Non-competitive inhibitors such as viral protease inhibitors. These drugs have also been used to treat Covid-19 infection in hospitalized patients, and their efficacy has been confirmed, e.g. Kaletra.(9) SARS coronavirus-1 virions infectivity reduce significantly in the weak acidic environment. (1,10) 5.1 . When Ammonium Chloride is metabolized in the liver, acidosis occurs in the lungs (11). Acidosis in the intracellular environment could inactivate the virus after proliferation and inhibit the initiation of the next cycle of infection in the patient (severity of the disease) or its infectivity (transmission and spread of the infection among individuals). Thus, besides the treatment of the disease, it could be effective in the control of Covid -19 infection. The severity of the infection in cases of reinfection and the mildness of the disease in children indicate that immune responses play an important role in complicating the infection. (12) Diphenhydramine compound is a generic drug used to control the clinical symptoms of respiratory infections. This drug has diphenhydramine, competitive inhibitor of histamine-1, which has a positive effect on the treatment of respiratory diseases. It also contains Ammonium Chloride. Ammonium Chloride will be effective in the control and treatment of Covid-19 infection in the following ways: By increasing the lysosomal pH and inhibiting the Cathepsin-L enzyme, it prevents the initiation of the virus replication cycle in the cell. By decreasing the pH of the intracellular environment in the patient's lung and causing acidosis, it could inactivate new viruses which replicated in the host, in addition to controlling infection in the patient, will likely reduce the spread of infection in the community. Covid-19 is associated with dry cough. Increased sputum is also effective pneumonia management, which greatly helps to relieve the symptoms. Ammonium Chloride as a sputter can also help in this matter. Therefore, given the availability of the drug, its safety in a variety groups of patients, diphenhydramine compound is suggested as a potential candidate for the treatment of Covid-19 infection as well as the control of its epidemy.