NMR solution structure of a potent cyclic nonapeptide inhibitor of ICAM‐1‐mediated leukocyte adhesion produced by homologous amino acid substitution

Sillerud, Laurel O.; Burks, Eric; Brown, William M.; Brown, David C.; Larson, Richard S.

doi:10.1111/j.1399-3011.2004.00176.x

Cited by 7 publications

(8 citation statements)

References 72 publications

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“…Other laboratories [85][86][87][88][89][90] have synthesized interface peptides based on the binding sequence for ICAM-1 derived from the crystal structure of the complex [91]. We have used NMR to determine the solution structure of our peptides [92], and have docked the most active molecules onto the surface of ICAM-1 in a manner which reveals additional details relevant for the understanding of the relationship between peptide structure and activity [93], particularly the importance of amino acid residues enriched at the sites of protein-protein interaction. Other β2 integrin inhibitors are being pursued after the discovery of an LLG interface peptide sequence [94].…”

Section: Resultsmentioning

confidence: 99%

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Sillerud¹,

Larson

2005

CPPS

118

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Peptides based on the amino acid sequences found at protein-protein interaction sites make excellent leads for antagonist development. A statistical picture of amino acids involved in protein-protein interactions indicates that proteins recognize and interact with one another through the restricted set of specialized interface amino acid residues, Pro, Ile, Tyr, Trp, Asp and Arg. These amino acids represent residues from each of the three classes of amino acids, hydrophobic, aromatic and charged, with one anionic and one cationic residue at neutral pH. The use of peptides as drug leads has been successfully used to search for antagonists of cell-surface receptors. Peptide, peptidomimetic, and non-peptide organic inhibitors of a class of cell surface receptors, the integrins, currently serve as therapeutic and diagnostic imaging agents. In this review, we discuss the structural features of protein-protein interactions as well as the design of peptides, peptidomimetics, and small organic molecules for the inhibition of protein-protein interactions. Information gained from studying inhibitors of integrin functions is now being applied to the design and testing of inhibitors of other protein-protein interactions. Most drug development progress in the past several decades has been made using the enzyme binding-pocket model of drug targets. Small molecules are designed to fit into the substrate-binding pockets of proteins based on a lock-and-key, induced-fit, or conformational ensemble model of the protein binding site. Traditionally, enzymes have been used as therapeutic drug targets because it was easier to develop rapid, sensitive screening assays, and to find low molecular weight inhibitors that blocked the active site. However, for proteins which interact with other proteins, rather than with small substrate molecules, the lack of binding pockets means that this approach will not generally succeed. There exist many diseases in which the inhibition of protein-protein interactions would provide therapeutic benefit, but there are no general methods available to address such problems. The focus of the first part of this review is to discuss the features of protein-protein interactions which may serve as general guidelines for the development and design of inhibitors for protein-protein interactions. In the second part we focus on the design of peptides (lead compounds) and their conversion into peptidomimetics or small organic molecules for the inhibition of protein-protein interactions. We draw examples from the important and emerging area of integrin-based cell adhesion and show how the principles of protein-protein interactions are followed in the discovery, optimization and usage of specific protein interface peptides as drug leads.

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Section: Resultsmentioning

confidence: 99%

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Sillerud¹,

Larson

2005

CPPS

118

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“…In fact, 10 of 11 peptides (group 4) with the greatest inhibition of SNV infectivity did not have significant sequence relatedness to SNV glycoproteins. Identification of inhibitory peptides that do not have significant sequence relatedness to native ligands has been described in other systems (35)(36)(37), and a large amount of work has indicated that nonhomologous amino acids may mimic the binding activities of each other (reviewed in reference 35). In addition, a comparison of the peptide sequences homologous with SNV to HTNV and PHV glycoproteins did not clearly identify possible contact points of FIG.…”

Section: Vol 79 2005 Peptide Inhibitors Of Snv Entry 7323mentioning

confidence: 99%

“…We chose this approach since we had previously used it successfully to identify inhibitory peptides of other integrin-ligand pairs (35)(36)(37). It is unclear what epitope on ␤ 3 integrin is recognized by ReoPro, and it is likely that antibodies are large enough to prevent interactions with regions well beyond the antibody's own epitope or the virus binding site on ␤ 3 .…”

Section: Vol 79 2005 Peptide Inhibitors Of Snv Entry 7323mentioning

confidence: 99%

Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β ₃ -Integrin Receptor

Larson¹,

Brown²,

Ye³

et al. 2005

J Virol

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Specific therapy is not available for the treatment of hantavirus cardiopulmonary syndrome caused by Sin Nombre virus (SNV). The entry of pathogenic hantaviruses into susceptible human cells is dependent upon expression of the ␣ v ␤ 3 integrin, and transfection of human ␤ 3 integrin is sufficient to confer infectibility onto CHO (Chinese hamster ovary) cells. Furthermore, pretreatment of susceptible cells with anti-␤ 3 antibodies such as c7E3 or its Fab fragment ReoPro prevents hantavirus entry. By using repeated selection of a cyclic nonamer peptide phage display library on purified ␣ v ␤ 3 , we identified 70 peptides that were competitively eluted with ReoPro. Each of these peptides was examined for its ability to reduce the number of foci of SNV strain SN77734 in a fluorescence-based focus reduction assay according to the method of Gavrilovskaya et al. (I. N. Gavrilovskaya, M. Shepley, R. Shaw, M. H. Ginsberg, and E. R. Mackow, Proc. Natl. Acad. Sci. USA 95:7074-7079, 1998). We found that 11 peptides reduced the number of foci to a greater extent than did 80 g/ml ReoPro when preincubated with Vero E6 cells. In addition, 8 of the 70 peptides had sequence similarity to SNV glycoproteins. We compared all 18 peptide sequences (10 most potent, 7 peptides with sequence similarity to hantavirus glycoproteins, and 1 peptide that was in the group that displayed the greatest potency and had significant sequence similarity) for their abilities to inhibit SNV, Hantaan virus (HTNV), and Prospect Hill virus (PHV) infection. There was a marked trend for the peptides to inhibit SNV and HTNV to a greater extent than they inhibited PHV, a finding that supports the contention that SNV and HTNV use ␤ 3 integrins and PHV uses a different receptor, ␤1 integrin. We then chemically synthesized the four peptides that showed the greatest ability to neutralize SNV. These peptides inhibited viral entry in vitro as free peptides outside of the context of a phage. Some combinations of peptides proved more inhibitory than did individual peptides. In all, we have identified novel peptides that inhibit entry by SNV and HTNV via ␤ 3 integrins and that can be used as lead compounds for further structural optimization and consequent enhancement of activity.

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“…Another set of interesting ICAM-1-targeting peptides are those derived, as in our work, from molecules that can bind to ICAM-1, such as certain sequences derived from MUC1 mucin core proteins (Hayashi et al, 2001), P(0) CAM (Jaafari and Foldvari, 2002), cyclic peptides derived from the ␣ L ␤ 2 integrin, leukocyte functional antigen-1 (Anderson and Siahaan, 2003;Sillerud et al, 2004). Most of these peptides have also been developed and tested in the context of blocking ICAM-1-mediated adhesion during inflammation and cancer metastasis and have been shown to bind to human ICAM-1 but have not been tested in other species.…”

Section: Discussionmentioning

confidence: 99%

A Fibrinogen-Derived Peptide Provides Intercellular Adhesion Molecule-1-Specific Targeting and Intraendothelial Transport of Polymer Nanocarriers in Human Cell Cultures and Mice

Garnacho¹,

Serrano²,

Muro³

2011

J Pharmacol Exp Ther

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Intercellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein expressed on activated endothelium and many other cells, represents a suitable target for delivery of drug nanocarriers (NCs) to disease areas. Numerous works have shown efficient targeting and intracellular transport of ICAM-1-targeted NCs, rendering significant therapeutic potential. This is the case for enzyme delivery for treatment of multitissue lysosomal storage disorders. However, those studies used formulations targeted to ICAM-1 by antibodies (anti-ICAM NCs). This poses an obstacle to preclinical evaluation of long-term treatment of such chronic maladies, caused by immunogenicity of foreign proteins administered to animals, compelling development of alternative strategies. In this work, we used radioisotope tracing, fluorescence and electron microscopy, and in vitro, cell cultures, and mouse models to evaluate polymer nanocarriers targeted to ICAM-1 by a 17-mer linear peptide derived from the ICAM-1-binding sequence of fibrinogen (␥3). Our results show that ␥3 NCs target ICAM-1 with efficiency and specificity similar to that of anti-ICAM NCs, determined by using immobilized ICAM-1, native ICAM-1 expressed on endothelial cell cultures, and intravenous administration in mice. Furthermore, ␥3 NCs are internalized by cells in culture and in vivo and transported to lysosomes via cell adhesion moleculemediated endocytosis, without apparent disruption of cell junctions, similar to anti-ICAM counterparts. The degree of conservation of fibrinogen ␥3 sequence and its cognate site on ICAM-1 among species (e.g., mouse, chimpanzee, and humans) reflects the interspecies targeting found for ␥3 NCs, providing an avenue for exploring the translation of ICAM-1-targeting platforms in the preclinical and, perhaps, future clinical realm.

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NMR solution structure of a potent cyclic nonapeptide inhibitor of ICAM‐1‐mediated leukocyte adhesion produced by homologous amino acid substitution

Cited by 7 publications

References 72 publications

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β ₃ -Integrin Receptor

A Fibrinogen-Derived Peptide Provides Intercellular Adhesion Molecule-1-Specific Targeting and Intraendothelial Transport of Polymer Nanocarriers in Human Cell Cultures and Mice

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NMR solution structure of a potent cyclic nonapeptide inhibitor of ICAM‐1‐mediated leukocyte adhesion produced by homologous amino acid substitution

Cited by 7 publications

References 72 publications

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β 3 -Integrin Receptor

A Fibrinogen-Derived Peptide Provides Intercellular Adhesion Molecule-1-Specific Targeting and Intraendothelial Transport of Polymer Nanocarriers in Human Cell Cultures and Mice

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Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β ₃ -Integrin Receptor