Design, Synthesis, and Biological Evaluation of α4β1 Integrin Antagonists Based on β-D-Mannose as Rigid Scaffold

Boer, Jürgen; Gottschling, Dirk; Schuster, Anja; Holzmann, Bernhard; Kessler, Horst

doi:10.1002/1521-3773(20011015)40:20<3870::aid-anie3870>3.3.co;2-o

Cited by 3 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These present studies also reconfirmed the necessity of β-orientation of the Asp side chain for activity, as found for the β-anomer of 11 toward the α4β1/VCAM-1 interaction . In fact, the α-anomer of 20 , as for the α-anomer of 11 , did not show any inhibitory activity.…”

Section: Resultssupporting

confidence: 86%

“…The mannose core mimicked the bioactive conformation of the constrained peptides, displaying the aspartic acid at the i + 1 position of a β-turn (Figure ). Unfortunately, the designed mannopyranoside had no inhibitory activity against α4β7/MAdCAM interaction, but one analogue where the Thr side chain is replaced by the Ser side chain demonstrated inhibition of VCAM-mediated binding of α4β1 Jurkat cells (IC 50 ≅ 3.7 mM) . Our interest in α4β7 integrin antagonists prompted us to investigate the possibility of changing the selectivity and enhancing the potency of this carbohydrate peptidomimetic, as well as of shortening the synthetic strategy.…”

Section: Introductionmentioning

confidence: 99%

“…Our interest in α4β7 integrin antagonists prompted us to investigate the possibility of changing the selectivity and enhancing the potency of this carbohydrate peptidomimetic, as well as of shortening the synthetic strategy.

1 Comparison between a lead peptidic inhibitor of the α4β7/MAdCAM interaction and the mannose-based peptidomimetic …”

Section: Introductionmentioning

confidence: 99%

“…Comparison between a lead peptidic inhibitor of the α4β7/MAdCAM interaction and the mannose-based peptidomimetic …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Synthesis and Structure−Activity Relationship of Mannose-Based Peptidomimetics Selectively Blocking Integrin α4β7 Binding to Mucosal Addressin Cell Adhesion Molecule-1

et al. 2003

Self Cite

View full text Add to dashboard Cite

As part of our ongoing research in the development of alpha4beta7 integrin antagonists, we are interested in peptidomimetics based on a rigid scaffold to allow the display of essential side chains in a suitable binding conformation while eliminating backbone amide bonds and therefore improving pharmacokinetic parameters of the drug. Except for a few examples, peptidomimetics scaffolds have only been moderately successful and often yield molecules that lack the potency of their peptide counterparts. However, we present herein a successful application of using a rigid scaffold. Starting from a mannopyranoside analogue previously discovered in our laboratory as an inhibitor of the alpha4beta1/vascular cell adhesion molecule interaction, a biased library of functionalized carbohydrates was developed. One compound emerged from this library as an active and selective antagonist toward the alpha4beta7/mucosal addressin cell adhesion molecule interaction. Conformational implications and the relevance of different pharmacophoric patterns will be discussed in order to explain the reverse selectivity and enhanced affinity.

show abstract

Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

1 Comparison between a lead peptidic inhibitor of the α4β7/MAdCAM interaction and the mannose-based peptidomimetic …”

Section: Introductionmentioning

confidence: 99%

“…Comparison between a lead peptidic inhibitor of the α4β7/MAdCAM interaction and the mannose-based peptidomimetic …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and Structure−Activity Relationship of Mannose-Based Peptidomimetics Selectively Blocking Integrin α4β7 Binding to Mucosal Addressin Cell Adhesion Molecule-1

et al. 2003

Self Cite

View full text Add to dashboard Cite

show abstract

“…Potential of Monovalent Aromatic Glycosyl Amides as Scaffolds. The use of carbohydrates as scaffolds in peptidomimetic and other research related to drug development has recently been explored by Hirschmann, Nicolaou, Smith, and co-workers and other researchers . The low bioavailability of peptide drugs has led to investigations of placing pharmacophoric groups on a nonpeptide scaffold; the scaffold can orient these groups in the direction of their respective binding subsites.…”

Section: Resultsmentioning

confidence: 99%

Development of Carbohydrate-Based Scaffolds for Restricted Presentation of Recognition Groups. Extension to Divalent Ligands and Implications for the Structure of Dimerized Receptors

et al. 2003

View full text Add to dashboard Cite

The solution structure of glycosyl amides has been studied by using NMR. A strong preference is displayed by tertiary aromatic glycosyl amides for E-anti structures in contrast with secondary aromatic glycosyl amides where Z-anti structures predominate. The structural diversity displayed by these classes of molecules would seem to be important as the directional properties of the aromatic ring, or groups attached to the aromatic ring, would be determined by choosing to have either a secondary or tertiary amide at the anomeric center and could be considered when designing bioactive molecules with carbohydrate scaffolds. The structural analysis was also carried out for related divalent secondary and tertiary glycosyl amides and these compounds display preferences similar to that of the monovalent compounds. The constrained divalent compounds have potential for promoting formation of clusters that will have restricted structure and thus have potential for novel studies of mechanisms of action of multivalent ligands. Possible applications of such compounds would be as scaffolds for the design and synthesis of ligands that will facilitate protein-protein or other receptor-receptor interactions. The affinity of restricted divalent (or higher order) ligands, designed to bind to proteins that recognize carbohydrates which would facilitate clustering and concomitantly promote protein-protein interactions, may be significantly higher than monovalent counterparts or multivalent ligands without these properties. This may be useful as a new approach in the development of therapeutics based on carbohydrates.

show abstract

Conformational Analysis of an α3β1 Integrin-Binding Peptide from Thrombospondin-1: Implications for Antiangiogenic Drug Design

et al. 2006

View full text Add to dashboard Cite

The integrin alpha3beta1 plays important roles in development, angiogenesis, and the pathogenesis of cancer, suggesting potential therapeutic uses for antagonists of this receptor. Recently, an alpha3beta1 integrin-binding site was mapped to residues 190-201 (FQGVLQNVRFVF) of the N-terminal domain of the secreted protein thrombospondin-1 (TSP1). This sequence displays diverse biological activities in vitro and inhibits angiogenesis in vivo. Herein we describe the NMR solution conformation of this segment in both water and dodecylphosphocholine micelles. While essentially unstructured in water, a more well-defined conformation is populated in micelles, particularly in the C-terminal half of the peptide and correlated with increased biological activity of the micellar peptide. The data suggested that the residues that are critical for biological activity are contained in a structurally well-defined segment of the peptide. These data support the role of the NVR motif as a required element of full-length TSP1 for specific molecular recognition by the alpha3beta1 integrin.

show abstract

Design, Synthesis, and Biological Evaluation of α4β1 Integrin Antagonists Based on β-D-Mannose as Rigid Scaffold

Cited by 3 publications

References 0 publications

Synthesis and Structure−Activity Relationship of Mannose-Based Peptidomimetics Selectively Blocking Integrin α4β7 Binding to Mucosal Addressin Cell Adhesion Molecule-1

Synthesis and Structure−Activity Relationship of Mannose-Based Peptidomimetics Selectively Blocking Integrin α4β7 Binding to Mucosal Addressin Cell Adhesion Molecule-1

Development of Carbohydrate-Based Scaffolds for Restricted Presentation of Recognition Groups. Extension to Divalent Ligands and Implications for the Structure of Dimerized Receptors

Conformational Analysis of an α3β1 Integrin-Binding Peptide from Thrombospondin-1: Implications for Antiangiogenic Drug Design

Contact Info

Product

Resources

About