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Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality 1 , 2 , 3 . Current interferon-based therapies 4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics 5 , 6 . The HCV-encoded NS3 protease is essential for viral replication 7 , 8 and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

In patients with HCV infection and no previous treatment, the addition of telaprevir to peginterferon–ribavirin resulted in higher response rates than those achieved with peginterferon–ribavirin alone. High rates of response were achieved with only 24 weeks of treatment. Patients with chronic hepatitis C virus (HCV) infection are at risk for progressive hepatic fibrosis, cirrhosis, portal hypertension, hepatic failure, and hepatocellular carcinoma. 1 – 4 For the past decade, treatment with pegylated interferon (peginterferon alfa) and ribavirin has been associated with rates of sustained virologic response of 40 to 50% among patients with HCV genotype 1 who had received no previous treatment. 5 – 7 At least 48 weeks of treatment is required for most of these patients, and toxic effects may limit the extent of treatment in some patients. 5 – 7 Telaprevir, a linear peptidomimetic HCV NS3/4A serine protease inhibitor, was associated with . . .

Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC50 0.24 μM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.

In this trial involving previously untreated patients infected with hepatitis C virus (HCV) genotype 1, boceprevir in combination with peginterferon and ribavirin was more effective than peginterferon and ribavirin alone. Anemia was a common adverse effect of boceprevir. Chronic infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide. 1 , 2 Rates of sustained virologic response associated with peginterferon–ribavirin therapy remain below 50% and are often less than 30% among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis, diabetes, coinfection with the human immunodeficiency virus (HIV), or African heritage. 3 – 9 Recent efforts to improve the rate of sustained virologic response have focused on oral direct-acting antiviral agents. 10 – 13 Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site. . . .

In this trial involving patients infected with hepatitis C virus (HCV) genotype 1 in whom previous treatment had failed, boceprevir plus peginterferon and ribavirin was more effective than peginterferon and ribavirin alone. Adverse effects of boceprevir included anemia and neutropenia. More than 170 million people are chronically infected with hepatitis C virus (HCV) worldwide. 1 The standard treatment is combination therapy with peginterferon and ribavirin. 2 – 4 Of the six HCV genotypes, genotype 1 is the least responsive to currently approved therapies, with rates of sustained virologic response of less than 50%. 2 , 5 – 7 Thus, there is a large population of patients with few therapeutic options, and direct-acting antiviral therapy has become the focus of investigations regarding treatment for HCV infection. 8 – 11 Boceprevir is a structurally novel peptidomimetic ketoamide protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site. . . .

In patients with HCV infection who did not have a sustained response to peginterferon plus ribavirin, the addition of telaprevir to this combination therapy was more effective than combination therapy alone. Adverse events with telaprevir included rash and anemia. Approximately 60% of patients who are infected with hepatitis C virus (HCV) genotype 1 are not cured by 48 weeks of peginterferon alfa combined with ribavirin. 1 Such patients fall into one of three categories: those who have no response to therapy, which is defined as a reduction of less than 2 log 10 in HCV RNA levels after 12 weeks of therapy 2 ; those who have a partial response, which is defined as a reduction of at least 2 log 10 in a patient who has always had detectable serum HCV RNA during therapy; and those who have a relapse, . . .

A new protein with immune properties was found in Galleria mellonella hemolymph. The so-far putative serine protease inhibitor dipetalogastin-like (GmSPID) was found in one fraction obtained after separation of hemolymph by RP-HPLC. Its amount depended on the immune status of the insect: it significantly increased after oral (10^3 CFU) and intrahemocelic (10 and 50 CFU) infection with entomopathogenic bacteria Pseudomonas entomophila . This was accompanied by up-regulation of the respective gene in the fat body of infected larvae. GmSPID was purified to homogeneity and characterised as a protein with immune properties. Among the three proteases tested, i.e. trypsin, elastase, and thermolysin, the strongest inhibition was observed toward trypsin. No inhibition toward the metalloproteinase thermolysin was detected, confirming that GmSPID is an inhibitor of serine proteases. Additionally, GmSPID was shown to have antimicrobial properties. At the concentration of 7 µM and 15 µM, it acted against Pseudomonas entomophila , Pseudomonas aeruginosa , Bacillus thuringiensis , Escherichia coli , and Candida albicans but not against Staphylococcus aureus . Moreover, with the use of atomic force, scanning, and transmission electron microscopy techniques, we present the effect of the GmSPID protein on the surface properties, shape, and ultrastructure of P. entomophila cells. The protein caused modest perforation of the cellular membrane, contributing to loss of its integrity. The mode of the GmSPID protein action as an antimicrobial compound and its role in G. mellonella immunity are discussed.

The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern 1 , 2 . Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern 3 , 4 . Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs) such as TMPRSS2; these proteases cleave the viral spike protein to expose the fusion peptide for cell entry, and thus have an essential role in the virus lifecycle 5 , 6 . Here we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of higher than 10 6 in inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids 7 . In Calu-3 cells it inhibits the entry of the SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Notably, in the K18-human ACE2 transgenic mouse model of severe COVID-19, we found that N-0385 affords a high level of prophylactic and therapeutic benefit after multiple administrations or even after a single administration. Together, our findings show that TTSP-mediated proteolytic maturation of the spike protein is critical for SARS-CoV-2 infection in vivo, and suggest that N-0385 provides an effective early treatment option against COVID-19 and emerging SARS-CoV-2 variants of concern. A small-molecule inhibitor of TMPRSS2 is effective against SARS-CoV-2 variants of concern in human lung cells and in donor-derived colonoids, and also shows prophylactic and therapeutic benefits in a mouse model of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of −14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.

In this randomized trial of patients infected with hepatitis C virus genotype 1 in whom a sustained virologic response was not achieved after initial therapy, patients retreated with peginterferon alfa-2a and ribavirin combined with telaprevir were more likely to have a sustained response than patients retreated with peginterferon alfa-2a and ribavirin alone. Patients retreated with peginterferon alfa-2a and ribavirin combined with telaprevir were more likely to have a sustained response than patients retreated with peginterferon alfa-2a and ribavirin alone. Worldwide, an estimated 170 million people have chronic hepatitis C virus (HCV) infection, and in many of these people, cirrhosis and complications of end-stage liver disease will develop. 1 , 2 Chronic HCV infection is the leading cause of liver disease and is the leading indication for liver transplantation in the United States and Europe. 3 Currently available treatment for HCV infection necessitates peginterferon alfa injections combined with oral ribavirin for 24 or 48 weeks (depending on the HCV genotype). 4 Overall, in 40 to 50% of patients infected with HCV genotype 1 who have not previously been treated, the currently available treatment results . . .