SARS-CoV-2, the virus that causes COVID-19, is prone to mutations and the generation of genetic variants. Since its first outbreak in 2019, SARS-CoV-2 has continually evolved, resulting in the emergence of several lineages and variants of concern (VOC) that have gained more efficient transmission, severity, and immune evasion properties. The World Health Organization has given these variants names according to the letters of the Greek Alphabet, starting with the Alpha (B.1.1.7) variant, which emerged in 2020, followed by the Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. This review explores the genetic variation among different VOCs of SARS-CoV-2 and how the emergence of variants made a global impact on the pandemic.

Antimicrobial resistance is an emerging global public health crisis, calling for urgent development of novel potent antibiotics. We propose that arsinothricin and related arsenic-containing compounds may be the progenitors of a new class of antibiotics to extend our antibiotic era.

Protein tyrosine (Y) nitration is an oxidative modification that occurs in pathological conditions such as neurodegenerative diseases and solid tumors. Depending on the location of the tyrosine residue, nitration can modify protein structure and function and affect cellular processes. We previously showed that site-specific nitration of the molecular chaperone heat shock protein 90 (Hsp90) leads to distinct pathological gain-of-function that cannot be compensated or overcome by native Hsp90. While Hsp90 nitrated on Y33 localizes in mitochondria and decreases mitochondrial metabolism, Hsp90 nitrated on Y56 activates the purinergic receptor and calcium channel P2X7, triggering downstream signaling pathways that can lead to either cell proliferation or apoptosis, depending on the cell type. Herein, using complementary biophysical, biochemical, and in silico methods, we show that nitration on Y33 and Y56 triggers significant site-dependent local and global structural changes linked to changes in Hsp90 activity. Nitration of these critical residues led to destabilization of Hsp90 dimer and formation of stable oligomeric species, with differential effects on Hsp90 ATPase and chaperone holdase activities depending on the nitrated residue. Molecular dynamics simulations further support the impact of nitration on Y33 and Y56 on the ATP-lid dynamics and the interaction of ATP with R392, critical to Hsp90 ATPase activity. Establishing the molecular basis of nitration-induced structural changes in Hsp90 leading to disease-driving functions is the first step toward the development of therapeutic approaches selectively targeting these pathological variants of Hsp90.

Hailey Hailey Disease (HHD) is an autosomal dominant cutaneous disorder caused by mutations in ATP2C1, the gene encoding the Golgi/secretory pathway Ca ²⁺ -ATPase SPCA1. Characterized by suprabasal acantholysis and intertriginous blistering of the skin, HHD treatment focuses on managing symptoms as there is no cure. Challenges to targeted therapy are due to the lack of facile and reliable models, both human and rodent, for mechanistic studies. Here we validate and characterize CRISPR/Cas9 mediated single and bi-allelic ATP2C1 knockouts in immortalized human hTERT keratinocytes. Whereas SPCA1 expression, Golgi morphology and Golgi Ca ²⁺ accumulation were proportionately affected in heterozygous and homozygous ATP2C1 null mutants as expected, both single and double allelic mutants showed near complete loss of cadherins associated with desmosomal and adherens junctions. HHD is characterized by poor wound healing and impaired keratinocyte migration. We show that SPCA1 is required for dynamic reorganization of actin cytoskeleton in keratinocyte spreading. We identified an insulin activated PI3K-AKT-Rac1 signaling pathway required for lamellipodia formation and keratinocyte spreading, defective in SPCA1 mutants. Transgenic expression of hSPCA1 or treatment with CDN1163, a small molecule Ca ²⁺ -ATPase agonist, restored defective phenotypes in the HHD model, paving the way for future therapeutic approaches to treat this disorder.