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Cell Chem Biol ; 29(5): 774-784.e8, 2022 May 19.
Article in English | MEDLINE | ID: covidwho-1616412


The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

COVID-19 , SARS-CoV-2 , Acriflavine , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Mice , Molecular Docking Simulation , Pandemics
Molecules ; 26(19)2021 Oct 07.
Article in English | MEDLINE | ID: covidwho-1463770


The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization.

Antiviral Agents/pharmacology , Arginine/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Rutin/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Coronavirus 3C Proteases/metabolism , Humans , Molecular Docking Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2/metabolism , Solubility
Sci Rep ; 11(1): 20012, 2021 10 08.
Article in English | MEDLINE | ID: covidwho-1462029


There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of - 3 to - 4 at a concentration of 10-100 µg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 µg/ mL (p < 0.05 compared to untreated controls). In vivo studies using transgenic mice expressing the ACE-2 receptor, dosed nasally with SARS-COV-2 (426,000 TCID50/mL) showed a trend for nasal GCPQ (20 mg/kg) to inhibit viral load in the respiratory tract and brain, although the study was not powered to detect statistical significance. GCPQ's electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 h after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.

Antiviral Agents/therapeutic use , COVID-19/drug therapy , Nasal Sprays , SARS-CoV-2/drug effects , A549 Cells , Animals , Antiviral Agents/administration & dosage , Chlorocebus aethiops , Humans , Male , Methylation , Mice, Inbred BALB C , Mice, Transgenic , SARS-CoV-2/physiology , Surface-Active Agents/administration & dosage , Surface-Active Agents/therapeutic use , Vero Cells , Viral Load/drug effects
Antioxidants (Basel) ; 10(9)2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1408381


COVID-19 caused by SARS-CoV-2 caused a worldwide crisis, highlighting the importance of preventive measures in infectious diseases control. SARS-CoV-2 can remain infectious on surfaces for up to several weeks; therefore, proper disinfection is required to mitigate the risk of indirect virus spreading. Gaseous ozone treatment has received particular attention as an easily accessible disinfection tool. In this study, we evaluated the virucidal effectiveness of gaseous ozone treatment (>7.3 ppm, 2 h) on murine hepatitis virus (MHV)-contaminated stainless-steel surface and PBS-suspended virus under field conditions at ambient (21.8%) and high (49.8-54.2%) relative humidity. Surficial virus was soiled with 0.3 g/L of BSA. Parallelly, a half-hour vaporization with 7.3% hydrogen peroxide was performed on contaminated carriers. The obtained results showed that gaseous ozone, whilst quite effective against suspended virus, was insufficient in sanitizing coronavirus contaminated surfaces, especially under low RH. Increased humidity created more favorable conditions for MHV inactivation, resulting in 2.1 log titre reduction. Vaporization with 7.3% hydrogen peroxide presented much better virucidal performance than ozonation in a similar experimental setup, indicating that its application may be more advantageous regarding gaseous disinfection of surfaces contaminated with other coronaviruses, including SARS-CoV-2.

Int J Mol Sci ; 22(13)2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1288904


The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 µM and 8 µM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.

Antiviral Agents/chemistry , Quercetin/chemistry , SARS-CoV-2/metabolism , Selenium/chemistry , Viral Matrix Proteins/antagonists & inhibitors , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Chlorocebus aethiops , Humans , Hydrogen Bonding , Molecular Docking Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Quercetin/metabolism , Quercetin/pharmacology , SARS-CoV-2/isolation & purification , Selenium/metabolism , Vero Cells , Viral Matrix Proteins/metabolism , Virus Replication/drug effects
J Virol ; 95(4)2021 01 28.
Article in English | MEDLINE | ID: covidwho-1054610


Among seven coronaviruses that infect humans, three (severe acute respiratory syndrome coronavirus [SARS-CoV], Middle East respiratory syndrome coronavirus [MERS-CoV], and the newly identified severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) are associated with a severe, life-threatening respiratory infection and multiorgan failure. We previously proposed that the cationically modified chitosan N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) is a potent inhibitor of human coronavirus NL63 (HCoV-NL63). Next, we demonstrated the broad-spectrum antiviral activity of the compound, as it inhibited all low-pathogenicity human coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1). Here, using in vitro and ex vivo models of human airway epithelia, we show that HTCC effectively blocks MERS-CoV and SARS-CoV-2 infection. We also confirmed the mechanism of action for these two viruses, showing that the polymer blocks the virus entry into the host cell by interaction with the S protein.IMPORTANCE The beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the health care measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of an HTCC compound, previously developed by us, which may be used as a potential inhibitor of currently circulating highly pathogenic coronaviruses-SARS-CoV-2 and MERS-CoV.

COVID-19/drug therapy , Chitosan/analogs & derivatives , Coronavirus Infections/drug therapy , Middle East Respiratory Syndrome Coronavirus/drug effects , Quaternary Ammonium Compounds/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19/epidemiology , COVID-19/virology , Chitosan/pharmacology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Respiratory Mucosa/drug effects , Respiratory Mucosa/virology , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects