Indomethacin: Can It Counteract Bradykinin Effects in COVID-19 Patients?

COVID-19 represents the biggest health challenge. Although the mortality rate of COVID-19 is low, the high numbers of infected people and those with post-COVID-19 symptoms represent a real problem for the health system. A high number of patients with COVID-19 or people recovered from COVID-19 suffer from a dry cough and/or myalgia. Interestingly, an imbalance in bradykinin was observed in COVID-19 patients, which might be due to the accumulation of bradykinin as a result of a reduction in the degradation of bradykinin. This finding inspired the idea of possible similitude between the dry cough that is induced by angiotensin-converting enzyme inhibitors and the COVID-19-induced dry cough. Both of these types of cough are mediated, at least partially, by bradykinin. They both manifested as a persistent dry cough that is not responded to traditional dry cough remedies. However, several drugs were previously investigated for the treatment of angiotensin-converting enzyme inhibitor-induced dry cough. Here, we hypothesized that such treatment might be useful in COVID-19-induced dry cough and other bradykinin-related symptoms such as generalized pain and myalgia. In this article, evidence was presented to support the use of indomethacin as a potential treatment of COVID-19-induced dry cough. The choice of indomethacin was based on its ability to suppress the cyclooxygenase enzyme while also lowering the level of the inflammatory mediator bradykinin. Furthermore, indomethacin has been shown to be effective in treating angiotensin-converting enzyme inhibitor-induced dry cough. Moreover, indomethacin is a long-established, low-cost, effective, and readily available medication.

Azithromycin and ambroxol as potential pharmacotherapy for SARS-CoV-2.

Knowing the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind to the angiotensin-converting enzyme 2 (ACE2) receptor and to enter cells via endocytosis paved the way for repositioning of old drugs as potential treatment of COVID-19, the disease caused by SARS-CoV-2 infection. This paper highlights the potential of azithromycin and ambroxol to treat COVID-19. Azithromycin and ambroxol share lysosomotropic characteristics, i.e. they penetrate and accumulate inside the late endosomes and lysosomes and may possibly interfere with multiplication of the virus inside cells. In addition, both of these drugs have anti-inflammatory effects. Ambroxol has a proven antiviral effect and a unique stimulatory action on the secretion of surfactant by alveolar type II cells, the main target of SARS-CoV-2. Surfactant may form a fundamental defence mechanism against the virus. Involvement of nasal epithelial cells in SARS-CoV-2 entry suggested advantageous use of inhaled drug delivery of these two drugs over the use of systemic administration. Inhaled drug delivery could aid in targeting the drug to the exact site of action with little or no side effects. To conclude, administration of these two drugs using a special drug delivery system provides two kinds of drug targeting: (i) tissue targeting through using an inhaled drug delivery system to achieve high drug concentrations at the respiratory epithelial tissue that overexpress the ACE2 receptor for virus binding; and (ii) cellular targeting of the virus in the acidic vesicles (late endosomes and lysosomes), which represent the fate of endocytic viruses.

On the cellular uptake and membrane effect of the multifunctional peptide, TatLK15.

Recently, the multifunctional peptide TatLK15 resulting from the fusion of the cell penetrating peptide Tat and the amphipathic peptide LK15 was shown to be efficient at mediating siRNA and shRNA delivery in leukemia cells to silence the bcr-abl oncoprotein. The present study focused on TatLK15 peptide cellular uptake and defining conditions for its use within a range of doses exhibiting minimal toxicity. The initial part of the study carried out in solution confirmed that the insertion of a glycine bridge allowed retention of the LK15 α-helicity, and fluorescence correlation spectroscopy did not reveal preferential conformations at the studied concentrations. In the second part, TatLK15 uptake mechanisms appeared peptide dose- and cell line- dependent as well as requiring membrane potential. Below a critical dose, TatLK15 toxicity appeared limited for approximately three hours as demonstrated by the combined use of lactate dehydrogenase release, MTT assays, and time-dependent observation of membrane-impermeant dye uptake using high content screening apparatus. Furthermore, toxicity was observed to occur rapidly at higher peptide doses. Finally, a comparison between TatLK15 and another Tat amphipathic peptide construct suggested that α-helix content should be viewed as a key element in the development of similar peptides.

Improved Tat-mediated plasmid DNA transfer by fusion to LK15 peptide.

The use of cell penetrating peptides (CPPs), such as Tat-derived peptide, to deliver DNA into cells is limited as evidenced by the low transfection efficiency of their DNA complexes. Here, we demonstrate that covalent attachment of membrane active peptide LK15 to Tat peptide improves gene transfer. Our results demonstrate that Tat peptide was able to form complexes with DNA, but their transfection efficiency was insufficient as assessed by luciferase assay. The attachment of LK15 to Tat significantly improved the physiochemical properties of the DNA complexes, rendered the complexes membrane active and enhanced the gene expression in HT29 and in HT1080 cultured cells. The enhanced transfection ability of Tat-LK15 compared to Tat is likely to be due mainly to the higher uptake of DNA. Finally, we evaluated the penetration and transfection ability of Tat and Tat-LK15 in multicellular tumour spheroids (MCTS) to mimic in vivo delivery to tumours. The results showed that the penetration and transfection ability of Tat and Tat-LK15/DNA complexes were limited to the rim of HT29 spheroids. Taken together, our data shows improvement in the transfection efficiency of Tat peptide by covalent attachment to LK15. Further advancements are needed before any potential applications in tissues as the penetration into the core of MCTS remains severely restricted.