Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor.

Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available.

David versus Goliath: Early career researchers in an unethical publishing system.

The publish-or-perish culture in academia has catalysed the development of an unethical publishing system. This system is characterised by the proliferation of journals and publishers-unaffiliated with learned societies or universities-that maintain extremely large revenues and profit margins diverting funds away from the academic community. Early career researchers (ECRs) are particularly vulnerable to the consequences of this publishing system because of intersecting factors, including pressure to pursue high impact publications, rising publication costs and job insecurity.

An open-access global database of meta-analyses investigating yield and biodiversity responses to different management practices.

We here present a database of evidence on the impact of agricultural management practices on biodiversity and yield. This database is the result of a systematic literature review, that aimed to identify meta-analyses that use as their response variables any measure of biodiversity and yield. After screening more than 1,086 titles and abstracts, we identified 33 relevant meta-analyses, from which we extracted the overall estimates, the subgroup estimates as well as all information related to them (effect size metric, taxonomic group, crop type etc.

A global database to catalogue the impacts of agricultural management practices on terrestrial biodiversity.

Habitat loss and degradation due to global agriculture land use is a major threat to biodiversity. Identifying agricultural management practices that mitigate these impacts is urgently needed. Thousands of experiments have been conducted worldwide in the last decades to compare the impacts of various agricultural management practices on biodiversity.

Discovery of Acyl-Indole Derivatives as Pan-Serotype Dengue Virus NS4B Inhibitors.

In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates and with improved pan-serotype coverage (EC's against the four DENV serotypes ranging from 0.

Blocking NS3-NS4B interaction inhibits dengue virus in non-human primates.

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million with annually around 10,000 deaths. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors.

From Oxetane to Thietane: Extending the Antiviral Spectrum of 2'-Spirocyclic Uridines by Substituting Oxygen with Sulfur.

In continuation of our efforts of finding novel nucleoside inhibitors for the treatment of viral diseases, we initiated a discovery research program aimed at identifying novel nucleos(t)ide inhibitors for emerging diseases like Dengue and Chikungunya. Based on the previously reported 2'-spiro-oxetane uridine derivatives active against Hepatitis C Virus (HCV), we envisaged its sulfur analogue as an interesting congener both from a synthetic as well as biological point of view. Surprisingly, we found the 2'-spirothietane uridine derivatives not only to be active against HCV and Dengue virus (DENV), viruses belonging to the flavivirus family, but also to demonstrate activity against alphaviruses like Chikungunya virus (CHIKV) and Sindbis virus (SINV).

Effect of Vitamin D Serum Levels and GC Gene Polymorphisms in Liver Fibrosis Due to Chronic Hepatitis C.

Introduction And Aim: Vitamin D has been associated with chronic liver diseases and low vitamin levels may contribute to progression of chronic hepatitis C. The aim of this study was to evaluate the influence of vitamin D serum levels and GC gene polymorphisms in the severity of liver fibrosis in patients with chronic hepatitis C genotype 1.

Material And Methods: Cross-sectional study that enrolled 132 adult patients with chronic hepatitis C genotype 1 attended at the outpatient Clinic of Gastroenterology Division at Hospital de Clínicas de Porto Alegre.

Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors Using Methyl α-Amino-β-fluoro-β-vinylcyclopropanecarboxylate as Key Intermediate.

Synthesis of fluorocyclopropyl building blocks, which constitute the core of various therapeutic agents against the hepatitis C virus, is described. The relevant methyl α-amino-β-fluoro-β-vinylcyclopropanecarboxylate has been used as a key intermediate for the total synthesis of a fluorinated analogue of Simeprevir (TMC 435), a HCV NS3/4A protease inhibitor.

Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model.

Background: The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI).

Methods: African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.

Development of a high-throughput antiviral assay for screening inhibitors of chikungunya virus and generation of drug-resistant mutations in cultured cells.

Chikungunya virus (CHIKV) is a mosquito-borne Alphavirus that has already infected millions of people in recent large-scale epidemics in Africa, the islands of the Indian Ocean, South and Southeast Asia, and northern Italy. The infection is still ongoing in many countries, such as India. Although the fatal rate is approximately 0.

Synthesis of fluorinated cyclopropyl amino acid analogues: toward the synthesis of original fluorinated peptidomimetics.

A straightforward, easy, and practical access to various amino acid analogues (methionine, leucine, lysine, and arginine) from a unique fluorinated cyclopropane scaffold is described. Moreover, the synthesis, for the first time, of one tripeptide incorporating a fluorinated cyclopropane amino acid (FCAA) analogue is reported.

Palladium catalyzed one-pot sequential Suzuki cross-coupling-direct C-H functionalization of imidazo[1,2-a]pyrazines.

An efficient "one-pot" selective functionalization at C3/C6 of imidazo[1,2-a]pyrazines has been developed via a palladium-catalyzed sequential Suzuki-Miyaura cross-coupling/direct C-H arylation, vinylation, and benzylation. The procedure remains effective in the presence of a methyl thioether group at C8, which may in turn be successfully engaged in a cross-coupling method to afford 3,6,8-trisubstituted imidazo[1,2-a]pyrazines. This work paves the way for the design of biologically relevant compounds in an imidazo[1,2-a]pyrazine series.

Detection of methicillin-resistant Staphylococcus aureus in clinical specimens from cystic fibrosis patients by use of chromogenic selective agar.

We evaluated the use of a chromogenic selective medium (MRSA ID) as a useful tool for the detection of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patient samples. Fifty-four MRSA isolates were detected by MRSA ID, while only 24/54 (44%) (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.

High vancomycin resistance among biofilms produced by Staphylococcus species isolated from central venous catheters.

Biofilm production is an important mechanism that allows microbes to escape host defences and antimicrobial therapy. Vancomycin has been used largely for the treatment of methicillin-resistant staphylococcal infections. Here, we determined the minimal inhibitory concentration (MIC) and minimal biofilm eradication concentration (MBEC) for 82 Staphylococcus species isolated from central venous catheters (CVC).

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model.

Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy.

Application of a feasible method for determination of biofilm antimicrobial susceptibility in staphylococci.

The aim of this study was to use a practical method to determine the minimal biofilm eradication concentration (MBEC) of vancomycin and to compare the MBEC with minimal inhibitory concentration (MIC) for biofilm-producing and non-biofilm-producing isolates of staphylococci. Forty Staphylococcus spp. isolates from central venous catheter, from distinct patients, were selected for this study.

Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein.

Six-helix bundle (6HB) formation is an essential step for many viruses that rely on a class I fusion protein to enter a target cell and initiate replication. Because the binding modes of small molecule inhibitors of 6HB formation are largely unknown, precisely how they disrupt 6HB formation remains unclear, and structure-based design of improved inhibitors is thus seriously hampered. Here we present the high resolution crystal structure of TMC353121, a potent inhibitor of respiratory syncytial virus (RSV), bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats.

Prospects for the development of fusion inhibitors to treat human respiratory syncytial virus infection.

Human respiratory syncytial virus (hRSV) is a significant cause of respiratory illness in at-risk pediatric patients, immunocompromised adults and the elderly. No vaccine is currently available for the virus and treatment options are limited to the prophylactic treatment of at-risk infants with the mAb palivizumab (Synagis) and to therapeutic intervention with the nucleoside analog ribavirin (Rebetol). The clinical use of these agents is limited and a need exists for more effective treatment for the at-risk population.

1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.

Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC(50)=400nM and 270nM, respectively) and selective (CC(50)>20muM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.

1,5-benzodiazepines, a novel class of hepatitis C virus polymerase nonnucleoside inhibitors.

The exogenous control of hepatitis C virus (HCV) replication can be mediated through the inhibition of the RNA-dependent RNA polymerase (RdRp) activity of NS5B. Small-molecule inhibitors of NS5B include nucleoside and nonnucleoside analogs. Here, we report the discovery of a novel class of HCV polymerase nonnucleoside inhibitors, 1,5-benzodiazepines (1,5-BZDs), identified by high-throughput screening of a library of small molecules.

Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121).

A preceding paper (Bonfanti et al. J. Med Chem.