Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines

Bhusal, Ram Prasad; Eaton, James R.O.; Chowdhury, Sayeeda Tasneem; Power, Christine; Proudfoot, Amanda E. I.; Stone, Martin J.; Bhattacharya, Shoumo

doi:10.1016/j.tibs.2019.10.003

Cited by 24 publications

(35 citation statements)

References 63 publications

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“…The structure of the gamma herpesvirus M3 protein also displays a novel structure capable of binding chemokines with high affinity [93]. These unique and highly potent virus-derived chemokine modulating proteins further demonstrate the central role of chemokines in immune response, not only for viruses but also in many other invasive organisms including ticks and helminths such as Schistosoma mansoni, that also produce CBPs [94,95]. This broad range of pathogen-produced CBPs again demonstrates the benefit of chemokine blockade by pathogens for evasion of host immune cell attack.…”

Section: Chemokine Binding Proteins (Cbps)mentioning

confidence: 88%

“…Potent immune modulators have been identified in many organisms. For example, Evasins are chemokine-binding proteins isolated from tick salivary glands [95]. Evasin-3 was effective as a treatment to reduce stroke in a mouse carotid occlusion model [195] and a single administration was found to prevent myocardial reperfusion injury in mice [196].…”

Section: Future Directionsmentioning

confidence: 99%

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Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Yaron

Zhang

Guo

et al. 2020

JCM

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Viruses are widely used as a platform for the production of therapeutics. Vaccines containing live, dead and components of viruses, gene therapy vectors and oncolytic viruses are key examples of clinically-approved therapeutic uses for viruses. Despite this, the use of virus-derived proteins as natural sources for immune modulators remains in the early stages of development. Viruses have evolved complex, highly effective approaches for immune evasion. Originally developed for protection against host immune responses, viral immune-modulating proteins are extraordinarily potent, often functioning at picomolar concentrations. These complex viral intracellular parasites have “performed the R&D”, developing highly effective immune evasive strategies over millions of years. These proteins provide a new and natural source for immune-modulating therapeutics, similar in many ways to penicillin being developed from mold or streptokinase from bacteria. Virus-derived serine proteinase inhibitors (serpins), chemokine modulating proteins, complement control, inflammasome inhibition, growth factors (e.g., viral vascular endothelial growth factor) and cytokine mimics (e.g., viral interleukin 10) and/or inhibitors (e.g., tumor necrosis factor) have now been identified that target central immunological response pathways. We review here current development of virus-derived immune-modulating biologics with efficacy demonstrated in pre-clinical or clinical studies, focusing on pox and herpesviruses-derived immune-modulating therapeutics.

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Section: Chemokine Binding Proteins (Cbps)mentioning

confidence: 88%

Section: Future Directionsmentioning

confidence: 99%

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Yaron

Zhang

Guo

et al. 2020

JCM

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“…The reason for this is thought to lie, at least in part, in the apparent redundancy within the chemokine network, which creates robustness ( 11 ). Natural selection in diverse pathogens including viruses ( 12 ), helminths ( 13 ), and ticks ( 14 ) has resulted in the convergent evolution of structurally unrelated proteins that bind multiple chemokines. This phenomenon suggests that the ability to target multiple chemokines is an effective strategy to disable the chemokine network and host defense mechanisms such as inflammation.…”

mentioning

confidence: 99%

“…Evasins fall into two classes: class A, exclusively binding CCL chemokines; and class B, exclusively binding C X CL chemokines (reviewed in Ref. 14 ). When administered parenterally, evasins have potent anti-inflammatory efficacy in preclinical disease models including myocardial ischemia and reperfusion injury, intestinal ischemia, colitis, acute pancreatitis, lung inflammation, arthritis, psoriasis, and graft- versus -host disease (reviewed in Ref.…”

mentioning

confidence: 99%

Engineered anti-inflammatory peptides inspired by mapping an evasin–chemokine interaction

Darlot

Eaton

Geis-Asteggiante

et al. 2020

Journal of Biological Chemistry

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Chemokines mediate leucocyte migration and homeostasis, and are key targets in inflammatory diseases including atherosclerosis, cytokine storm and chronic auto-immune disease. Chemokine redundancy and ensuing network robustness has frustrated therapeutic development. Salivary evasins from ticks bind multiple chemokines overcoming redundancy, and are effective in several pre-clinical disease models. Their clinical development has not progressed due to concerns regarding potential immunogenicity, parenteral delivery and cost. Peptides mimicking protein activity can overcome the perceived limitations of therapeutic proteins. Here we show that peptides possessing multiple-chemokine-binding and anti-inflammatory activities can be developed from the chemokine-binding site of an evasin. We used hydrogen–deuterium exchange mass spectrometry to map the binding interface of the evasin P672 that physically interacts with C-C motif chemokine ligand 8 (CCL8) and synthesized a 16-mer peptide (BK1.1) based on this interface region in evasin P672. Fluorescent polarization and native mass spectrometry approaches showed that BK1.1 binds CCL8, CCL7 and CCL18, and disrupts CCL8 homodimerization. We show that a BK1.1 derivative, BK1.3, has substantially improved ability to disrupt P672 binding to CCL8, CCL2 and CCL3 in an AlphaScreen assay. Using isothermal titration calorimetry, we show that BK1.3 directly binds CCL8. BK1.3 also has substantially improved ability to inhibit CCL8, CCL7, CCL2 and CCL3 chemotactic function in vitro. We show that local as well as systemic administration of BK1.3 potently blocks inflammation in vivo. Identification and characterization of the chemokine-binding interface of evasins could thus inspire the development of novel anti-inflammatory peptides that therapeutically target the chemokine network in inflammatory diseases.

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“…Salp16 Iper1 and Salp16 Iper2 (Figure 2), salivary proteins from Ixodes persulcatus, have been shown to have anti-IL-8 activity, thereby impairing neutrophil chemotaxis (76). A very recent review summarized the data on Evasins, which are secreted by hard ticks and bind to host chemokines to inhibit their activation of chemokine receptors (77). Of the Evasins, three from Rhipicephalus sanguineus (Evasin-1, -3, and -4) were selective for different chemokines (78).…”

Section: Recruitment Of Blood-borne Innate Immune Cellsmentioning

confidence: 99%

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

et al. 2020

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Immunodeficiency disorders and autoimmune diseases are common, but a lack of effective targeted drugs and the side-effects of existing drugs have stimulated interest in finding therapeutic alternatives. Naturally derived substances are a recognized source of novel drugs, and tick saliva is increasingly recognized as a rich source of bioactive molecules with specific functions. Ticks use their saliva to overcome the innate and adaptive host immune systems. Their saliva is a rich cocktail of molecules including proteins, peptides, lipid derivatives, and recently discovered non-coding RNAs that inhibit or modulate vertebrate immune reactions. A number of tick saliva and/or salivary gland molecules have been characterized and shown to be promising candidates for drug development for vertebrate immune diseases. However, further validation of these molecules at the molecular, cellular, and organism levels is now required to progress lead candidates to clinical testing. In this paper, we review the data on the immunopharmacological aspects of tick salivary compounds characterized in vitro and/or in vivo and present recent findings on non-coding RNAs that might be exploitable as immunomodulatory therapies.

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Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines

Cited by 24 publications

References 63 publications

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Engineered anti-inflammatory peptides inspired by mapping an evasin–chemokine interaction

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

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