Target-Induced Horseradish Peroxidase Deactivation for Multicolor Colorimetric Assay of Hydrogen Sulfide in Rat Brain Microdialysis

Hydrogen sulfide (H₂S) is important for normal neural functions, which involves protecting neurons from oxidative stress and neuronal transmission modulation in brain. The detection of H₂S is significant for revealing its role in the diagnosis of various disease. In this study, a novel multicolor colorimetric assay based on the etching of gold nanorods (Au NRs) is proposed to evaluate H₂S level with the naked eye. This measurement relies on the catalytic oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) via horseradish peroxidase (HRP) to produce TMB²⁺, which could etch the Au NRs quickly and accompany with a distinct color change. The vivid colors can be easily distinguished with the naked eye without any sophisticated instruments. The presence of H₂S can cause the deactivation of HRP, which affects the amount of TMB²⁺ produced and consequently affects the color changing of the system. Based on this mechanism, a simple but sensitive multicolor colorimetric assay is developed for H₂S detection with a linear range of 0.05–50 μM. The proposed method is demonstrated for monitoring extracellular H₂S in rat brain coupled with microdialysate

Map of district-level trachoma prevalence surveys included in the cost analysis.

<p>Map of district-level trachoma prevalence surveys included in the cost analysis.</p

Summary of total costs, by observation.

<p>Summary of total costs, by observation.</p

Average proportion of total survey costs attributed to cost categories and activities.

<p>Average proportion of total survey costs attributed to cost categories and activities.</p

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropyl­acylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound <b>35</b> which demonstrated antiviral activity in HCV-infected patients

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (<b>2</b>) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to <b>2</b>, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like <b>2</b>, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (<b>1</b>) from clinical trials. Structure–activity relationships (SARs) at each of the structural subsites in <b>2</b> were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (<b>29</b>)