Peptide based inhibitors of interleukin-8: structural simplification and enhanced potency

Attwood, Michael R.; Conway, Elizabeth A.; Dunsdon, R.; Greening, John R.; Handa, B.K.; Jones, Philip S.; Jordan, Steven C.; Keech, Elizabeth; Wilson, Francis X.

doi:10.1016/s0960-894x(97)00036-x

Cited by 19 publications

(13 citation statements)

References 9 publications

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“…T-lymphocytes, monocytes, endothelial cells, epithelial cells, and neutrophils) in response to a variety of stimuli, e.g. lipopolysaccharides (LPS), IL-1, and tumor necrosis factor (TNF) 12,13 . Raised levels of IL-8 have been detected in several disease states 14 , and experiments using monoclonal antibodies have indicated that inhibition of the action of this chemokine in some models of disease can lead to beneficial effects 13,15 .…”

Section: Introductionmentioning

confidence: 99%

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity againstEscherichia coli-induced interleukin-8 production

Xiong

Chen

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity againstEscherichia coli-induced interleukin-8 production

Xiong

Chen

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Some CXCL8-binding peptides have been proposed to inhibit CXCL8 binding to human neutrophils 26 27 . In addition, a peptide derived from two short sequence motifs of the N-terminus of CXCR1 linked by a general sequence was verified as high affinity for CXCL8 binding 28 29 . However, to the best of our knowledge, no report exists regarding the peptide inhibition of CXCL8 binding to CXCR1.…”

mentioning

confidence: 99%

Peptides derived from CXCL8 based on in silico analysis inhibit CXCL8 interactions with its receptor CXCR1

Jiang

Liou

Chang

et al. 2015

Sci Rep

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Chemokine CXCL8 is crucial for regulation of inflammatory and immune responses via activating its cognate receptor CXCR1. In this study, molecular docking and binding free energy calculations were combined to predict the initial binding event of CXCL8 to CXCR1 for peptide drug design. The simulations reveal that in the initial binding, the N-loop of CXCL8 interacts with the N-terminus of CXCR1, which is dominated by electrostatic interactions. The derived peptides from the binding region of CXCL8 are synthesized for further confirmation. Surface plasmon resonance analyses indicate that the CXCL8 derived peptide with 14 residues is able to bind to the receptor CXCR1 derived peptide with equilibrium KD of 252 μM while the peptide encompassing a CXCL8 K15A mutation hardly binds to CXCR1 derived peptide (KD = 1553 μM). The cell experiments show that the designed peptide inhibits CXCL8-induced and LPS-activated monocytes adhesion and transmigration. However, when the peptides were mutated on two lysine residues (K15 and K20), the inhibition effects were greatly reduced indicating these two amino acids are key residues for the initial binding of CXCL8 to CXCR1. This study demonstrates that in silico prediction based functional peptide design can be effective for developing anti-inflammation drugs.

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“…CXCR1 and CXCR2 are the specific receptors of CXCL8. N-terminal peptides of CXCR1 have been shown to prevent CXCL8 from binding to CXCR1 and hence act as inhibitors of the signaling cascade [ 18 , 19 ]. In this study, the N-terminal peptide derived from CXCR1 [ 10 ] was titrated into 15 N-labeled hG31P to a final molar ratio of 3:1 ( Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, the N-terminal peptide derived from CXCR1 [ 10 ] was titrated into 15 N-labeled hG31P to a final molar ratio of 3:1 ( Figure 5 A). Residues Leu15, Asn16, Phe17, Thr18 and Gly19 of the wild-type CXCR1 N-terminal sequence were replaced by a single 6-aminohexanoic acid moiety in this N-terminal CXCR1 peptide [ 19 ]. The reason to choose this peptide was due to its small size and potency of inhibition of CXCL8 receptor binding [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

“…Residues Leu15, Asn16, Phe17, Thr18 and Gly19 of the wild-type CXCR1 N-terminal sequence were replaced by a single 6-aminohexanoic acid moiety in this N-terminal CXCR1 peptide [ 19 ]. The reason to choose this peptide was due to its small size and potency of inhibition of CXCL8 receptor binding [ 19 ]. It also allows us to compare the NMR results with the previous peptide/CXCL8 complex studies [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

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Effects of K11R and G31P Mutations on the Structure and Biological Activities of CXCL8: Solution Structure of Human CXCL8(3-72)K11R/G31P

Cheng

Gordon

et al. 2017

Molecules

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The ELR-CXC chemokines are important to neutrophil inflammation in many acute and chronic diseases. Among them, CXCL8 (interleukin-8, IL-8), the expression levels of which are elevated in many inflammatory diseases, binds to both the CXCR1 and CXCR2 receptors with high affinity. Recently, an analogue of human CXCL8, CXCL8(3–72)K11R/G31P (hG31P) has been developed. It has been demonstrated that hG31P is a high affinity antagonist for both the CXCR1 and CXCR2. Herein, we have determined the solution structure and the CXCR1 N-terminal peptide binding sites of hG31P by NMR spectroscopy. We have found that the displacement within the tertiary structure of the 30 s loop and the N-terminal region and more specifically change of the loop conformation (especially H33), of hG31P may affect its binding to the CXCR1 receptor and thereby inhibit human neutrophil chemotactic responses induced by ELR-CXC chemokines. Our results provide a structural basis for future clinical investigations of this CXCR1/CXCR2 receptor antagonist and for the further development of CXCL8 based antagonists.

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Peptide based inhibitors of interleukin-8: structural simplification and enhanced potency

Cited by 19 publications

References 9 publications

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity againstEscherichia coli-induced interleukin-8 production

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity againstEscherichia coli-induced interleukin-8 production

Peptides derived from CXCL8 based on in silico analysis inhibit CXCL8 interactions with its receptor CXCR1

Effects of K11R and G31P Mutations on the Structure and Biological Activities of CXCL8: Solution Structure of Human CXCL8(3-72)K11R/G31P

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