After one year of the COVID-19 pandemic and hundreds of suggested drugs, will cathepsin L inhibitors be the solution?

Cysteine cathepsins are defined as lysosomal enzymes that are members of the papain family. Cysteine cathepsins (Cts) prevalently exist in whole organisms, varying from prokaryotes to mammals, and possess greatly conserved cysteine residues in their active sites. Cts are engaged in the digestion of cellular proteins, activation of zymogens, and remodeling of the extracellular matrix (ECM). Host cells are entered by SARS-CoV-2 via endocytosis. Cathepsin L and phosphatidylinositol 3-phosphate 5-kinase are crucial in endocytosis by cleaving the spike protein, which permits viral membrane fusion with the endosomal membrane and succeeds in the release of the viral genome to the host cell. Therefore, inhibition of cathepsin L may be advantageous in terms of decreasing infection caused by SARS-CoV-2. Coordinate inhibition of multiple Cts and lysosomal function by different drugs and biological agents might be of value for some purposes, such as a parasite or viral infections and antineoplastic applications. Zn2+ deficiency or dysregulation leads to exaggerated cysteine cathepsin activity, increasing the autoimmune/inflammatory response. For this purpose, Zn2+ metal can be safely combined with a drug that increases the anti-proteolytic effect of endogenous Zn2+, lowering the excessive activity of some CysCts. Biguanide derivative complexes with Zn2+ have been found to be promising inhibitors of CysCts protease reactions. Molecular docking studies of cathepsin L inhibited by the metformin-Zn+2 complex have been performed, showing two strong key interactions (Cys-25&His-163) and an extra H-bond with Asp-163 compared to cocrystallized Zn+2 (PDB ID 4axl).

Correlation between Micronutrient plasma concentration and disease severity in COVID-19 patients

Objectives: Coronavirus Disease 2019 (COVID-19) is caused by a new strain of betacoronavirus called SARS-CoV-2, which leads to mild to severe symptoms. Micronutrients in blood serum, namely, zinc, iron, copper, and selenium, play essential roles in the human body's various organs. This study investigates the association between micronutrient levels and the severity of symptoms in SARS-CoV-2 infected patients. Methods: A cross-section study was conducted during June-August 2020 in Riyadh city among 80 patients with confirmed SARS-CoV-2 infection. Within 24 hours of hospital admission, patients have been divided into non-severe and severe cases, and blood samples were drawn from each patient to measure the serum levels of copper, iron "in the form of ferritin," selenium, and zinc. Results: In both study groups, the mean copper and selenium serum levels were within the normal range, while the mean zinc and iron serum levels were elevated. A statistically significant difference was recorded between non-severe and severe cases regarding serum levels of iron and selenium (331.24 vs. 1174.95 ng/ml and 134 vs. 162 mcg/L, respectively, P < 0.0001). On the other hand, no significant difference was detected between both studied groups regarding serum level of zinc and copper (124.57 vs. 116.37 mcq/L and 18.35 vs. 18.2 mcmol/L, respectively, P > 0.05). Conclusions: There was a significant elevation of selenium and iron serum levels among severe cases compared to non-severe cases of COVID-19. High levels of iron and selenium could be correlated with the disease severity during infection with SARS-CoV-2.