Halogen bonding has emerged at the forefront of advances in improving ligand: receptor interactions. In particular the newfound ability of this extant non-covalent-bonding phenomena has revolutionized computational approaches to drug discovery while simultaneously reenergizing synthetic approaches to the field. Here we survey, via examples of classical applications involving halogen atoms in pharmaceutical compounds and their biological hosts, the unique advantages that halogen atoms offer as both Lewis acids and Lewis bases.

Endoplasmic reticulum (ER) proteins including protein disulfide isomerase (PDI) are playing crucial roles in maintaining appropriate protein folding. Under nitrosative stress, an excess of nitric oxide (NO) radical species induced the S-nitrosylation of PDI cysteines which eliminate its isomerase and oxidoreductase capabilities. In addition, the S-nitrosylation-PDI complex is the cause of aggregation especially of the α-synuclein (α-syn) protein (accumulation of Lewy-body aggregates). We recently identified a potent antioxidant small molecule, Ferrostatin-1 (Fer-1), that was able to inhibit a non-apoptotic cell death named ferroptosis. Ferroptosis cell death involved the generation of oxidative stress particularly lipid peroxide. In this work, we reported the neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells (SH-SY5Y). We first synthesized the Fer-1 and confirmed that it is not toxic toward the SH-SY5Y cells at concentrations up to 12.5 μM. Second, we showed that Fer-1 compound quenched the commercially available stable radical, the 2,2-diphenyl-1-picrylhydrazyl (DPPH), in non-cellular assay at 82 %. Third, Fer-1 inhibited the ROS/RNS generated under rotenone insult in SH-SY5Y cells. Fourth, we revealed the effective role of Fer-1 in ER stress mediated activation of apoptotic pathway. Finally, we reported that Fer-1 mitigated rotenone-induced α-syn aggregation.

The synthesis and characterization of a family of [60]fullerocurcuminoids obtained via Bingel reactions is reported.

Until the recent past, the sole exemplar of proteins as infectious agents leading to neurodegenerative disorders remained the prion protein. Since then, the self-seeding mechanism characteristic of the prion protein has also been attributed to other neurodegenerative-disease-associated proteins, including amyloid-β (Aβ), tau, and α-synuclein (α-Syn). In model cell line studies, truncated Aβ, viz. amyloid beta (25–35), has been found to influence cellular homeostasis through its interactions with, and via, the disruption of key housekeeping machinery. Here, we demonstrate that the incubation of human neuroblastoma (SH-SY5Y) cell line with Brazilin ((6aS,11bR)-7,11b-dihydro-6H-indeno­[2,1-c]­chromene-3,6a,9,10-tetrol) prior to Aβ (25–35)-insult protected the cells from oxidative stress and apoptotic cell death. Furthermore, Brazilin mitigated Aβ-induced alterations in protein disulfide isomerase (PDI) and α-synuclein status, both of which are important biomarkers that report on Parkinson’s pathogenesis. The results obtained in this study suggest that the tetrol is neuroprotective and helps resist Aβ-induced cross-pathology and amyloidogenic onset.

Human cell survival requires function of the Na+/K+ pump; the heteromeric protein that hydrolyzes ATP to extrude Na+ and import K+ across the plasmalemma, thereby building and maintaining their electrochemical gradients. Numerous dominant diseases caused by mutations in genes encoding for Na+/K+ pump catalytic (α) subunit isoforms highlight the importance of this protein. Here, we review literature describing disorders caused by missense mutations in ATP1A1, the gene encoding the ubiquitously expressed α1 isoform of the Na+/K+ pump. These various maladies include primary aldosteronism with secondary hypertension, an endocrine syndrome, Charcot-Marie-Tooth disease, a peripheral neuropathy, complex spastic paraplegia, another neuromuscular disorder, as well as hypomagnesemia accompanied by seizures and cognitive delay, a condition affecting the renal and central nervous systems. This article focuses on observed commonalities among these mutations' functional effects, as well as on the special characteristics that enable each particular mutation to exclusively affect a certain system, without affecting others. In this respect, it is clear how somatic mutations localized to adrenal adenomas increase aldosterone production without compromising other systems. However, it remains largely unknown how and why some but not other de novo germline or familial mutations (where the mutant must be expressed in numerous tissues) produce a specific disease and not the others. We propose hypotheses to explain this observation and the approaches that we think will drive future research on these debilitating disorders to develop novel patient-specific treatments by combining the use of heterologous protein-expression systems, patient-derived pluripotent cells, and gene-edited cell and mouse models.