In response to infection or injury, the body mounts an inflammatory immune response in order to neutralize pathogens and promote tissue repair. The key effector cells for these responses are the leukocytes (white blood cells), which are specifically recruited to the site of injury. However, dysregulation of the inflammatory response, characterized by the excessive migration of leukocytes to the affected tissues, can also lead to chronic inflammatory diseases. Leukocyte recruitment is regulated by inflammatory mediators, including an important family of small secreted chemokines and their corresponding G protein‐coupled receptors expressed in leukocytes. Unsurprisingly, due to their central role in the leukocyte inflammatory response, chemokines and their receptors have been intensely investigated and represent attractive drug targets. Nonetheless, the full therapeutic potential of chemokine receptors has not been realized, largely due to the complexities in the chemokine system. The determination of chemokine–receptor structures in recent years has dramatically shaped our understanding of the molecular mechanisms that underpin chemokine signaling. In this review, we summarize the contemporary structural view of chemokine–receptor recognition, and describe the various binding modes of peptide and small‐molecule ligands to chemokine receptors. We also provide some perspectives on the implications of these data for future research and therapeutic development.Importance Statement: Given their central role in the leukocyte inflammatory response, chemokines and their receptors are considered as important regulators of physiology and viable therapeutic targets. In this review, we provide a summary of the current understanding of chemokine: chemokine–receptor interactions that have been gained from structural studies, as well as their implications for future drug discovery efforts.

Fifteen fruits commonly used by the ethnic population in Nepal were studied for the antioxidant activity and total polyphenol content (TPC). Among them, Terminalia bellirica, Terminalia chebula, Phyllanthus emblica and Spondias pinnata were the most potent antioxidants as compared with vitamin C based on the 1,1-diphenyl-2-picryl hydrazyl radical assay. These fruits also contained high TPCs. Spondias pinnata, Pyrularia edulis, Melastoma malabathricum, Cipadema bacifera and Choerospondias axillaries fruits were evaluated for the first time. Moreover, Spondias pinnata was found to be more potent (16% radical scavenging activity at 5 μg/ml) than vitamin C (5% radical scavenging activity at 5 μg/ml). Antioxidant activity showed correlation to TPC with the correlation coefficients (R²) as 0.7189 and 0.7246 for the methanol and water extracts, respectively. This study suggests that a number of these fruits may have the potential to confer beneficial health effects due to their antioxidant activity and TPC.

Isocitrate lyase is important for lipid utilisation byMycobacterium tuberculosisbut its ICL2 isoform is poorly understood. Here we report that binding of the lipid metabolites acetyl-CoA or propionyl-CoA to ICL2 induces a striking structural rearrangement, substantially increasing isocitrate lyase and methylisocitrate lyase activities. Thus, ICL2 plays a pivotal role regulating carbon flux between the tricarboxylic acid (TCA) cycle, glyoxylate shunt and methylcitrate cycle at high lipid concentrations, a mechanism essential for bacterial growth and virulence.

Blood-feeding arthropods produce antiinflammatory salivary proteins called evasins that function through inhibition of chemokine-receptor signaling in the host. Herein, we show that the evasin ACA-01 from theAmblyomma cajennensetick can be posttranslationally sulfated at two tyrosine residues, albeit as a mixture of sulfated variants. Homogenously sulfated variants of the proteins were efficiently assembled via a semisynthetic native chemical ligation strategy. Sulfation significantly improved the binding affinity of ACA-01 for a range of proinflammatory chemokines and enhanced the ability of ACA-01 to inhibit chemokine signaling through cognate receptors. Comparisons of evasin sequences and structural data suggest that tyrosine sulfation serves as a receptor mimetic strategy for recognizing and suppressing the proinflammatory activity of a wide variety of mammalian chemokines. As such, the incorporation of this posttranslational modification (PTM) or mimics thereof into evasins may provide a strategy to optimize tick salivary proteins for antiinflammatory applications.

Ticks are hematophagous arachnids that parasitize mammals and other hosts, feeding on their blood. Ticks secrete numerous salivary factors that enhance host blood flow or suppress the host inflammatory response. The recruitment of leukocytes, a hallmark of inflammation, is regulated by chemokines, which activate chemokine receptors on the leukocytes. Ticks target this process by secreting glycoproteins called Evasins, which bind to chemokines and prevent leukocyte recruitment. This review describes the recent discovery of numerous Evasins produced by ticks, their classification into two structural and functional classes, and the efficacy of Evasins in animal models of inflammatory diseases. The review also proposes a standard nomenclature system for Evasins and discusses the potential of repurposing or engineering Evasins as therapeutic anti-inflammatory agents.