Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections.

Streptococcal toxic shock-like syndrome (STSLS) likely occurs when an individual is infected with the Streptococcus suis (S. suis) epidemic strain and is characterized by a cytokine storm, multiple organ dysfunction syndrome (MODS) and a high incidence of mortality despite adequate treatment. A number of antibiotics exhibit excellent bactericidal effects in vivo, such as fluoroquinolones, aminoglycosides (gentamicin) and ß-lactams (penicillin G, ceftiofur, or amoxicillin), but are less effective for treating STSLS. Therefore, there is an urgent need to identify new compounds that can reduce the damage caused by STSLS. In the present study, we identified auranofin, an orally bioavailable FDA-approved anti-rheumatic drug as a candidate repurposed drug to treat severe S. suis infections. Our results showed that auranofin can bind to the functional domain of bacterial thioredoxin reductase, decreasing the reducing redox-responsive capacity of target bacteria and allowing for the killing of S. suis cells. We also observed that auranofin has antibacterial activity against other gram-positive bacteria, such as multidrug resistant Streptococcus pneumoniae (MDRSP), Streptococcus agalactiae, and vancomycin-resistant strains of Staphylococcus aureus. Additionally, auranofin is capable of eradicating intracellular S.suis present inside infected macrophage cells. Mouse model experimental results showed that auranofin could effectively reduce the mortality of mice infected with S. suis. Compared to the ampicillin treatment group, the survival rate of mice in the auranofin treatment group in severely infected model mice was significantly improved. These results suggest that auranofin has the potential for use as an effective antibiotic against S. suis.

Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs.

Gold compounds have a long tradition in medicine and offer many opportunities for new therapeutic applications. Herein, we evaluated the lead compound Auranofin and five related gold(I) complexes as possible inhibitors of SARS-CoV-2 Main Protease (SARS-CoV-2 Mpro), a validated drug target for the COVID-19 disease. The investigational panel of gold compounds included Auranofin; three halido analogues, i.e., Au(PEt3)Cl, Au(PEt3)Br, and Au(PEt3)I; and two gold carbene complexes, i.e., Au(NHC)Cl and [Au(NHC)2]PF6. Notably, all these gold compounds, with the only exception of [Au(NHC)2]PF6, turned out to be potent inhibitors of the catalytic activity of SARS-CoV-2 Mpro: the measured Ki values were in the range 2.1-0.4 µM. The reactions of the various gold compounds with SARS-CoV-2 Mpro were subsequently investigated through electrospray ionization (ESI) mass spectrometry (MS) upon a careful optimization of the experimental conditions; the ESI MS spectra provided clear evidence for the formation of tight metallodrug-protein adducts and for the coordination of well defined gold-containing fragments to the SARS-CoV-2 Mpro, again with the only exception of [Au(NHC)2]PF6, The metal-protein stoichiometry was unambiguously determined for the resulting species. The crystal structures of the metallodrug- Mpro adducts were solved in the case of Au(PEt3)Br and Au(NHC)Cl. These crystal structures show that gold coordination occurs at the level of catalytic Cys 145 in the case of Au(NHC)Cl and at the level of both Cys 145 and Cys 156 for Au(PEt3)Br. Tight coordination of gold atoms to functionally relevant cysteine residues is believed to represent the true molecular basis of strong enzyme inhibition.

COVID-19: causes, mechanisms and possible treatments

At the end of 2019 in December, a bunch of deadly pneumonia cases were found in Huanan sea food market in city of Wuhan in Hubei province, china. They were caused by a previously unknown corona virus. All patients had been associated with the Wuhan Whole food market, where seafood and live animals are sold. The virus spread at an alarming speed and lead authorities in China to initiate effort and investigation. However, by that time, the great row of travelers had carried the virus to many countries, sparking memories of the previous corona virus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and causing widespread media attention and panic. Based on clinical criteria and available serological and molecular information, the new disease was called corona virus disease of 2019 (COVID-19), and the novel corona virus was called SARS Corona virus -2 (SARS-CoV-2), emphasizing its close relationship to the 2002 SARS virus (SARS-CoV). The scientific community raced to uncover the origin of the virus, understand the pathogenesis of the disease, develop treatment options, define the risk factors, and work on vaccine development. In this manuscript we portray the causes, mechanisms and possible treatments for corona virus.

In Vitro Anti-SARS-CoV-2 Activity of Selected Metal Compounds and Potential Molecular Basis for Their Actions Based on Computational Study.

Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl3), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3, and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed.

Auranofin: Past to Present, and repurposing.

Auranofin (AF), a gold compound, has been used to treat rheumatoid arthritis (RA) for more than 40 years; however, its mechanism of action remains unknown. We revealed that AF inhibited the induction of proinflammatory proteins and their mRNAs by the inflammatory stimulants, cyclooxygenase-2 and inducible nitric oxide synthase, and their upstream regulator, NF-κB. AF also activated the proteins peroxyredoxin-1, Kelch-like ECH-associated protein 1, and NF-E2-related factor 2, and inhibited thioredoxin reductase, all of which are involved in oxidative or electrophilic stress under physiological conditions. Although the cell membrane was previously considered to be permeable to AF because of its hydrophobicity, the mechanisms responsible for transporting AF into and out of cells as well as its effects on the uptake and excretion of other drugs have not yet been elucidated. Antibodies for cytokines have recently been employed in the treatment of RA, which has had an impact on the use of AF. Trials to repurpose AF as a risk-controlled agent to treat cancers or infectious diseases, including severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019, are ongoing. Novel gold compounds are also under development as anti-cancer and anti-infection agents.

Will Auranofin Become a Golden New Treatment Against COVID-19?

Auranofin is an FDA-approved disease-modifying anti-rheumatic drug that has been used for decades for treatment of rheumatoid arthritis. This gold(I) compound has anti-inflammatory properties because it reduces IL-6 expression via inhibition of the NF-κB-IL-6-STAT3 signaling pathway. Also, by inhibiting redox enzymes such as thioredoxin reductase, auranofin increases cellular oxidative stress and promotes apoptosis. Auranofin also possesses antiviral properties. Recently, it was reported that auranofin reduced by 95% SARS-CoV-2 RNA in infected human cells in vitro and decreased SARS-CoV-2-induced cytokine expression, including IL-6. During SARS-CoV-2 infection, a cytokine storm involving IL-6 increases severity of illness and worsens prognosis. Therefore, auranofin could, in our point of view, reduce pathology due to SARS-CoV-2-induced IL-6. COVID-19 is a rapidly-evolving respiratory disease now distributed worldwide. Strikingly high numbers of new COVID-19 cases are reported daily. We have begun a race to vaccinate people, but due to the complex logistics of this effort, the virus will continue to spread before all humans can be immunized, and new variants that may be less well contained by current vaccines are of concern. The COVID-19 pandemic has overwhelmed health care systems and new treatments to reduce mortality are urgently needed. We encourage to further evaluate the potential of auranofin in the treatment of COVID-19 in vitro and in animal models of SARS-CoV-2 infection and, if preliminary data are promising, in clinical trials with COVID-19 patients. In our opinion, auranofin has the potential to become a valuable addition to available therapies in this pandemic.

Identification of COVID-19 prognostic markers and therapeutic targets through meta-analysis and validation of Omics data from nasopharyngeal samples.

BACKGROUND: While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. Exploring host response to COVID-19 in the upper respiratory tract can unveil prognostic markers and therapeutic targets. METHODS: We conducted a meta-analysis of published transcriptome and proteome profiles of respiratory samples of COVID-19 patients to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swabs from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Guided by this analysis, we sought to check for potential drug targets. An FDA-approved drug, Auranofin, was tested against SARS-CoV-2 replication in cell culture and Syrian hamster challenge model. FINDINGS: The meta-analysis and validation in the COVID-19 cohort revealed S100 family genes (S100A6, S100A8, S100A9, and S100P) as prognostic markers of severe COVID-19. Furthermore, Thioredoxin (TXN) was found to be consistently upregulated. Auranofin, which targets Thioredoxin reductase, was found to mitigate SARS-CoV-2 replication in vitro. Furthermore, oral administration of Auranofin in Syrian hamsters in therapeutic as well as prophylactic regimen reduced viral replication, IL-6 production, and inflammation in the lungs. INTERPRETATION: Elevated mRNA level of S100s in the nasal swabs indicate severe COVID-19 disease, and FDA-approved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model. FUNDING: This study was supported by the DBT-IISc partnership program (DBT (IED/4/2020-MED/DBT)), the Infosys Young Investigator award (YI/2019/1106), DBT-BIRAC grant (BT/CS0007/CS/02/20) and the DBT-Wellcome Trust India Alliance Intermediate Fellowship (IA/I/18/1/503613) to ST lab.

Metallo therapeutics for COVID-19. Exploiting metal-based compounds for the discovery of new antiviral drugs.

INTRODUCTION: The COVID-19 pandemic poses an unprecedented challenge for the rapid discovery of drugs against this life-threatening disease. Owing to the peculiar features of the metal centers that are currently used in medicinal chemistry, metallodrugs might offer an excellent opportunity to achieve this goal. AREAS COVERED: Two main strategies for developing metal-based drugs against the SARS-CoV-2 are herein illustrated. Firstly, a few clinically approved metallodrugs could be evaluated in patients according to a 'drug repurposing' approach. To this respect, the gold drug auranofin seems a promising candidate, but some other clinically established metal compounds are worthy of a careful evaluation as well. On the other hand, libraries of inorganic compounds, featuring a large chemical diversity, should be screened to identify the most effective molecules. This second strategy might be assisted by a pathway-driven discovery approach arising from a preliminary knowledge of the mode of action, exploitable to inhibit the functional activities of the key viral proteins. Also, attention must be paid to selectivity and toxicity issues. EXPERT OPINION: The medicinal inorganic chemistry community may offer a valuable contribution against COVID-19. The screening of metallodrugs' libraries can expand the explored 'chemical space' and increase the chance of finding effective anti-COVID agents.

Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike-ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics*.

Gold complexes have a long tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effects have been confirmed. Herein, we evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targets of severe acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugs were effective inhibitors of the interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2 (ACE2) host receptor and might thus interfere with the viral entry process. The gold metallodrugs were also efficient inhibitors of the papain-like protease (PLpro) of SARS-CoV-1 and SARS-CoV-2, which is a key enzyme in the viral replication. Regarding PLpro from SARS-CoV-2, the here reported inhibitors are among the very first experimentally confirmed examples with activity against this target enzyme. Importantly, the activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to remove zinc ions from the labile zinc center of the enzyme. Taken together, the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.

The FDA-approved gold drug auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells.

SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 h after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its antiviral, anti-inflammatory and anti-reactive oxygen species (ROS) properties. Further animal studies are warranted to evaluate the safety and efficacy of auranofin for the management of SARS-COV-2 associated disease.