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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 . . .

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 emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19) 1 . The development of a vaccine is likely to take at least 12–18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose–response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod 2 – 4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from H9 human embryonic stem cell lines, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19. A screen of the ReFRAME library of approximately 12,000 known drugs for antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) identified several candidate compounds with suitable activities and pharmacological profiles, which could potentially expedite the deployment of therapies for coronavirus disease 2019 (COVID-19).

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, . . .

Incompletely infiltrated collagen fibrils in acid-etched dentin are susceptible to degradation. We hypothesize that degradation can occur in the absence of bacteria. Partially demineralized collagen matrices (DCMs) prepared from human dentin were stored in artificial saliva. Control specimens were stored in artificial saliva containing proteolytic enzyme inhibitors, or pure mineral oil. We retrieved them at 24 hrs, 90 and 250 days to examine the extent of degradation of DCM. In the 24-hour experimental and 90- and 250-day control specimens, we observed 5- to 6-μm-thick layers of DCM containing banded collagen fibrils. DCMs were almost completely destroyed in the 250-day experimental specimens, but not when incubated with enzyme inhibitors or mineral oil. Functional enzyme analysis of dentin powder revealed low levels of collagenolytic activity that was inhibited by protease inhibitors or 0.2% chlorhexidine. We hypothesize that collagen degradation occurred over time, via host-derived matrix metalloproteinases that are released slowly over time.

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.

Amphibian venom-derived peptides have high potential in the field of anticancer drug discovery. We have isolated a novel Bowman-Birk proteinase inhibitor (BBI)-type peptide from the skin secretion of Pelophylax esculentus (PE) named PE-BBI, and evaluated its bio-functions and anti-cancer activity in vitro . PE-BBI is a heptadecapeptide with C-terminal amidation. The mRNA sequence and primary structure of PE-BBI were identified using RT-PCR and LC/MS, respectively. A trypsin inhibitory assay was used to characterize the serine proteinase inhibitory activity of synthetic PE-BBI. PE-BBI’s myotropic activity was analyzed using isolated rat bladder and rat-tail artery smooth muscle tissues, and the anti-cancer ability of PE-BBI using human colorectal cancer cells. PE-BBI’s mechanism of action was investigated using Discovery studio software. PE-BBI showed trypsin inhibitory activity (K i  = 310 ± 72 nM), strong myotropic activity, and cytotoxicity that were specific to cancer cells, and no side effect to normal epithelial cells. The docking stimulation showed that PE-BBI had high affinity to several members of human kallikrein related peptidase (KLK) family. This finding helps to enrich our understanding of BBI peptides’ mode of action. Moreover, the data presented here validates frog secretions as sources of potential novel proteinase inhibitors for cancer treatment.