ABSTRACT
Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin’s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight significantly reduces the viral load in the trachea. Our results show that the inhibition of cathepsins, a protein family of the host organism, is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections. An intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets.
Subject(s)
Virus Diseases , Severe Acute Respiratory Syndrome , Carcinoma, Renal CellABSTRACT
Introduction: SARS-CoV-2 has caused a pandemic of historic proportions and continues to spread worldwide. Currently, there is no effective therapy against this virus. This article evaluated the in vitro antiviral effect of Atorvastatin against SARS-CoV-2 and also identified the interaction affinity between Atorvastatin and three SARS-CoV-2 proteins, using in silico structure-based molecular docking approach. Materials and methods: The antiviral activity of Atorvastatin against SARS-CoV-2 was evaluated by three different treatment strategies using a clinical isolate of SARS-CoV-2. The interaction of Atorvastatin with Spike, RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) was evaluated by molecular docking. Results: Atorvastatin showed anti-SARS-CoV-2 activity of 79%, 54.8%, 22.6% and 25% at 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by pre-post-treatment strategy. In addition, atorvastatin demonstrated an antiviral effect of 26.9% at 31.2 {micro}M by pre-infection treatment. This compound also inhibited SARS-CoV-2 in 66.9%, 75%, 27.9% and 29.2% at concentrations of 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by post-infection treatment. The interaction of atorvastatin with SARS-CoV-2 Spike, RdRp and 3CL protease yielded a binding affinity of -8.5 Kcal/mol, -6.2 Kcal/mol, and -7.5 Kcal/mol, respectively. Conclusion: Our study demonstrated the in vitro anti-SARS-CoV-2 activity of Atorvastatin, mainly against the late steps of the viral replicative cycle. A favorable binding affinity with viral proteins by bioinformatics methods was also shown. Due to its low cost, availability, well-established safety and tolerability, and the extensive clinical experience of atorvastatin, it could prove valuable in reducing morbidity and mortality from COVID-19.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
The coronavirus disease 2019 (COVID-19) has become a serious problem for public health since it was identified in the province of Wuhan (China) and spread around the world producing high mortality rates and economic losses. Nowadays, WHO recognizes traditional, complementary, and alternative medicine for treating COVID-19 symptoms. Therefore, we investigated the antiviral potential of the hydroalcoholic extract of Uncaria tomentosa stem bark from Peru against SARS-CoV-2 in vitro. The antiviral activity of U. tomentosa against SARS-CoV-2 in vitro was assessed in Vero E6 cells using cytopathic effect (CPE) and plaque reduction assay. After 48h of treatment, U. tomentosa showed an inhibition of 92.7 % of SARS-CoV-2 at 25.0 g/mL (p<0.0001) by plaque reduction assay on Vero E6 cells. In addition, U. tomentosa, induced a reduction of 98.6 % (p=0.02) and 92.7 % (p=0.03) in the CPE caused by SARS-CoV-2 on Vero E6 cells at 25 g/mL and 12.5 g/mL, respectively. The EC50 calculated for U. tomentosa extract by plaque reduction assay was 6.6 g/mL (4.89 - 8.85 g/mL) for a selectivity index of 4.1. The EC50 calculated for U. tomentosa extract by TCID50 assay was 2.57 g/mL (1.05 - 3.75 g/mL) for a selectivity index of 10.54. These results showed thatU. tomentosa known as Cat's claw has antiviral effect against SARS-CoV-2 observed as a reduction in the viral titer and CPE after 48h of treatment on Vero E6 cells. Therefore, we hypothesized that U. tomentosa stem bark, could be promissory to the development of new therapeutic strategies against SARS-CoV-2.