Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation: An Emerging Therapeutic Approach for Preeclampsia

Proteinuria is one of the hallmarks of preeclampsia (PE) that differentiates other hypertensive disorders of pregnancy. Protein misfolding and aggregation is an emerging pathological condition underlying many chronic metabolic diseases and neurodegenerative diseases. Recent studies indicate protein aggregation as an emerging biomarker of preeclampsia, wherein several proteins are aggregated and dysregulated in the body fluids of preeclamptic women, provoking the multi-systemic clinical manifestations of the disease. At the cellular level, these misfolded and aggregated proteins are potentially toxic interfering with the normal physiological process, eliciting the unfolded protein response (UPR) pathway activators in the endoplasmic reticulum (ER) that subsequently augments the ER quality control systems to remove these aberrant proteins. ER resident chaperones, folding enzymes and other proteins serve as part of the ER quality control machinery in restoring nascent protein folding. These ER chaperones are crucial for ER function aiding in native protein folding, maintaining calcium homeostasis, as sensors of ER stress and also as immune modulators. Consequently, ER chaperones seems to be involved in many cellular processes, yet the association is expanding to be explored. Understanding the role and mechanism of ER chaperones in regulating protein misfolding and aggregation would provide new avenues for therapeutic intervention as well as for the development of new diagnostic approaches

Inhibition of <i>mecA</i> and <i>bla_CTX-M</i> from MRSA and ESBL strains of diabetic foot infection by screening antibiotics compound library: an <i>in silico</i> analysis

A computational approach was exploited towards new molecule designing to target the inhibition of resistant genes mecA and blaCTX-M in MRSA and ESBL strains cultured from diabetic foot infected patients. The bioinformatic analysis involves the prediction of protein structures for mecA and blaCTX-M employing the Prime module of Schrodinger. The interactions were examined with the control antibiotics using the modelled protein structures, which revealed that Cefixime and Amikacin showed the highest binding affinity with mecA and blaCTX-M, respectively. According to the predictions of pharmacophores, the ADHRN hypothesis for mecA protein and the ADHR hypothesis for blaCTX-M protein were obtained. Subsequently, the antibiotic compound library from Selleckchem was retrieved, and molecular interactions studies were carried out to explore the interaction profiling of mecA with Tobramycin and blaCTX-M with Acyclovir. Further, the stability of protein-ligand interactions was validated through molecular dynamics simulations. Overall, this study suggests that the predicted pharmacophore model provides in-depth knowledge for repurposing an antibiotic drug with effective inhibition to enhance its therapeutic activity in the currently used ones. Communicated by Ramaswamy H. Sarma</p