Inhibition of a viral enzyme by a small-molecule dimer disruptor.

We identified small-molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi's sarcoma-associated herpesvirus (KSHV) by screening an alpha-helical mimetic library. Next, we synthesized a second generation of low-micromolar inhibitors with improved potency and solubility. Complementary methods including size exclusion chromatography and 1H-13C HSQC titration using selectively labeled 13C-Met samples revealed that monomeric protease is enriched in the presence of inhibitor. 1H-15N HSQC titration studies mapped the inhibitor binding site to the dimer interface, and mutagenesis studies targeting this region were consistent with a mechanism where inhibitor binding prevents dimerization through the conformational selection of a dynamic intermediate. These results validate the interface of herpesvirus proteases and other similar oligomeric interactions as suitable targets for the development of small-molecule inhibitors

Assessing Groundwater Quality for Sustainable Drinking and Irrigation: A GIS-Based Hydro-Chemical and Health Risk Study in Kovilpatti Taluk, Tamil Nadu

The continuous investigation of water resources is essential to assess pollution risks. This study investigated a groundwater assessment in the coastal belt of Tamil Nadu’s Kovilpatti Taluk, Thoothukudi district. Twenty-one groundwater samples were collected during the pre-monsoon and post-monsoon seasons, analyzing water quality parameters, namely pH, EC, Cl−, SO42−, Ca2+, Mg2+, HCO3−, TH, Na2+, and K+. The Water Quality Index (WQI) was computed and it is observed that 5% of pre-monsoon and 9% of post-monsoon samples were unsuitable for drinking. SAR, MHR, RSC, %Na and Kelley’s index were used to determine irrigation suitability. Pre-monsoon shows 29% (MHR) and 71% (RSC) unsuitable, and post-monsoon shows 59% (MHR) and 9% (RSC) unsuitable. Coastal activity, urbanization, and industrialization in Kovilpatti resulted in the degradation of groundwater quality. Solving this coastal issue requires sustainable wastewater treatment and strict industrial discharge guidelines. Spatial distribution plots, Box plots, Gibbs plots, Piper plots, Wilcox plots and Correlation Matrices had similar results to the computed WQI and its physical–chemical parameters. According to the human health risk assessment, the Mooppanpatti, Illuppaiurani, and Vijayapuri regions show high health risks due to the nitrate and fluoride concentration in the groundwater. Kadambu, Melparaipatti, Therkuilandhaikulam, and Vadakku Vandanam have low levels, posing a minimal health risk

Inhibition of a viral enzyme by a small-molecule dimer disruptor

Small molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi’s sarcoma-associated herpesvirus (KSHV) were identified by screening an α-helical mimetic library. Subsequently, a second generation of low micromolar inhibitors with improved potency and solubility was synthesized. Complementary methods including size exclusion chromatography and (1)H-(13)C HSQC titration using selectively labeled (13)C-Met samples revealed that monomeric protease is enriched in the presence of inhibitor. (1)H-(15)N-HSQC titration studies mapped the inhibitor binding-site to the dimer interface, and mutagenesis studies targeting this region were consistent with a mechanism where inhibitor binding prevents dimerization through the conformational selection of a dynamic intermediate. These results validate the interface of herpesvirus proteases and other similar oligomeric interactions as suitable targets for the development of small molecule inhibitors