"Repurposed Nystatin to Inhibit SARS-Cov-2 and Mutants in the GI Tract"

Abstract

The SARS-CoV-2 infections are considered as respiratory system diseases, mostly. In COVID-19, it might also be the infection of gastrointestinal (GI) tract too, especially at patients in severe clinical condition. SARS-CoV-2 can destroy the intestinal barrier, capable to spread into internal organs via blood and/or lymphatic circulation, and to cause serious damage there. Infected GI tract of COVID-19 patients is ideal environment for the coronavirus infection, replication and as virus reservoir might be the major source of pandemic reinfections, too. The process of virus budding is dependent on the host cell lipid rafts containing membrane-sterols, mainly cholesterol. The viral envelope may be challenged by polyene antibiotics, such as nystatin, which has strong affinity to sterols. Nystatin may block the establishment of the virus-host cell connection, too. In this study, the nystatin was investigated, as antiviral agent to SARS-CoV-2. We demonstrated by tests in Vero E6 cell based cytopathic assay, nystatin blocked the replication of SARS-CoV-2 in concentration 62.5 µg/ml (IC50) at Wuhan and British mutant strains. No efficient SARS-CoV-2 antiviral agent is known so far to alleviate pandemic, to disinfect GI tract, where vaccines might have limited effect, only. Nystatin might be the first one with emergency use authorization, either, as a safe and efficient non-systemic antiviral drug, with well-established use since decades.Diarrhea has been listed as a symptom of COVID-19 in the guideline

Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?

“…Similarly, as the CLIC/GEEC (CG) pathway involves plasma membrane cholesterol, 7-keto-cholesterol inhibits CLIC/GEEC-mediated viral entry as it prevents the close packing of acyl chains and affects the structure of the cell membrane. In a similar manner, the antifungal drug Nystatin and vinblastine were utilized based on their role in cholesterol withdrawal [ 119 ]. Furthermore, inhibitors of plasma membrane ruffle formation, an early step in micropinocytosis, such as flubendazole, terfenadine, itraconazole, vinblastine and imipramine, block the entry of viruses into the host cells [ 71 , 120 ].…”

Considerations of Nystatin Roll in Oral Candidiasis Scenario and the COVID-19 Pandemic—A Review

“…Virág et al ( 2021) [32] investigated the effect of antivirals against the SARS-CoV-2 virus by testing them in Vero E6 cell-based cytopathic assays on Wuhan and British mutant strains. The mechanism of this effect involves the binding of nystatin to cholesterol found in the plasma membrane of the cell host.…”

“…The viral envelope fusion with the plasma membrane of the cell host occurs for the entry of the virus. Therefore, in the post-pandemic scenario where novel strains of the SARS-CoV-2 virus have been reported, NYS should be investigated as an alternative use [32].…”

“…NYS was discovered in the 1950s by Hazen and Brown [32][33][34][35]. In therapeutics, NYS has been employed for many years, demonstrating its safety and efficacy with good pharmacological action; however, few relevant adverse effects are reported.…”

“…These chemical characteristics are usually associated with its low permeability, which prevents it from crossing intestinal cells when administered orally. Finally, this molecule has carboxylic and amino groups, which leads to pKa: 3.62 (acidic) and 9.11 (basic) [32,[40][41][42].…”