Potent cyclic peptide inhibitors of VLA-4 (?4?1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-d-Arg-d-Arg) (ZD7349) compatible with depot formulation

Dutta, Anand S.; Gormley, James J.; Coath, Matthew; Hassall, Lorraine; Hayward, Christopher F.; Gellert, Paul; Kittlety, Rod S.; Alcock, Peter; Ferguson, Roger K.; Halterman, Tracy; Jamieson, Alec; Moors, Jackie; Moores, Julie M.; Rees, Amanda; Wood, Linda J.; Reilly, Christopher F.; Haworth, Duncan

doi:10.1002/1099-1387(200008)6:8<398::aid-psc270>3.0.co;2-1

Cited by 21 publications

(4 citation statements)

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“…The key residues in VCAM-1 (QIDSP) and CS1 (EILDVP) necessary for their interactions with α4β1 have been defined by molecular and biochemical techniques ( , ). Many groups have used these sequences as starting points to develop small molecule inhibitors that can block the interaction between α4β1 and its ligands ( − ).…”

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confidence: 99%

Comparative Assessment of the Ligand and Metal Ion Binding Properties of Integrins α9β1 and α4β1

et al. 2002

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Integrins alpha9beta1 and alpha4beta1 form a distinct structural class, but while alpha4beta1 has been subjected to extensive study, alpha9beta1 remains poorly characterized. We have used the small molecule N-(benzenesulfonyl)-(L)-prolyl-(L)-O-(1-pyrrolidinylcarbonyl)tyrosine (3) to investigate the biochemical properties of alpha9beta1 and directly compare these properties with those of alpha4beta1. Compound 3 has a high affinity for both integrins with K(D) values of < or =3 and 180 pM for alpha9beta1 in 1 mM Mn2+ (activating) and 1 mM Ca2+ and 1 mM Mg2+ (nonactivating) conditions and < or =5 and 730 pM for alpha4beta1 under the corresponding conditions. Ca2+ treatment promoted the binding of 3 to both integrins (EC50 = 30 microM Ca2+ in both cases). Compound 3 binding to both integrins was also stimulated by the addition of the activating monoclonal antibody TS2/16. These findings indicate that the mechanisms by which metal ions and TS2/16 regulate ligand binding to alpha9beta1 and alpha4beta1 are similar. The binding of 3 to both integrins induced the mAb 9EG7 LIBS epitope, a property consistent with occupancy of the receptor's ligand binding site by 3. But whereas EGTA treatment inhibited the binding of 9EG7 to alpha4beta1, it stimulated the binding of 9EG7 to alpha9beta1. The 9EG7 and TS2/16 effects point to contributions of the beta1-chains on binding. Cross-linking data revealed that the integrin alpha-chains are also involved in binding the small molecule, as stable linkages were observed on both the alpha9 chain of alpha9beta1 and the alpha4 chain of alpha4beta1. Extensive structure-activity analyses with natural and synthetic ligands indicate distinct features of the ligand binding pockets. Most notable was the estimated >1000-fold difference in the affinity of the integrins for VCAM-1, which binds alpha4beta1with an apparent K(D) of 10 nM and alpha9beta1 with an apparent K(D) of >10 microM. Differences were also seen in the binding of alpha9beta1 and alpha4beta1 to osteopontin. Compound 3 competed effectively for the binding of VCAM-1 and osteopontin to both integrins. While these studies show many similarities in the biochemical properties of alpha9beta1 and alpha4beta1, they identify important differences in their structure and function that can be exploited in the design of selective alpha9beta1 and alpha4beta1 inhibitors.

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confidence: 99%

Comparative Assessment of the Ligand and Metal Ion Binding Properties of Integrins α9β1 and α4β1

et al. 2002

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“…However, further improvement in stability (pH 3) and other formulation characteristics will be required if the compounds are to be administered in slow-release formulations. Studies in progress have resulted in more potent and stable compounds with much improved release profiles from the depot formulations [41].…”

Section: Discussionmentioning

confidence: 99%

Potent Cyclic Monomeric and Dimeric Peptide Inhibitors of VLA-4 (?4?1 Integrin)-Mediated Cell Adhesion Based on the Ile-Leu-Asp-Val Tetrapeptide

et al. 2000

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“…30,31 For example, surface expression of VLA-4 has been shown to be essential for the entry of T-cell clones into the brain, 32 and in a number of different EAE models treatment with anti-VLA-4 monoclonal antibodies has been effective in suppressing the clinical signs of disease and T cell infiltration into the CNS. [32][33][34][35] Peptide blockers of VLA-4 have likewise been shown to be effective in EAE, 36 preventing the development of clinical signs and cellular infiltration. 37 Direct in vivo evidence has suggested that VLA-4 may be important not only in the capture and adhesion of T cells to microvascular endothelium through interaction with VCAM-1, 38 but also in facilitation of T-cell entry into the brain parenchyma (by the induction of metalloproteinase-2) and in maintenance of the residency of T cells within the CNS.…”

Section: Examples Of Novel Therapeutic Challenges For Msmentioning

confidence: 99%

Developing therapeutics for the treatment of multiple sclerosis

Virley

2005

Neurotherapeutics

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Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for clinical application. Preclinical animal models of MS provide the necessary test bed for evaluating the effects of novel therapeutic strategies. Because the clinical manifestations and pathological consequences of disease vary dramatically from individual to individual, as well as treatment response to existing therapies, this creates a significant research endeavor in terms of translating preclinical methodologies to the clinical domain. Potentially exciting treatments have emerged in the form of natalizumab (Tysabri), an alpha4 integrin antagonist, and more recently FTY720, a sphinogosine-1 phosphate receptor modulator, providing a compelling proof-of-principle from bench to bedside. However, further research is required to discharge safety concerns associated with these therapeutic avenues. Future prospects in the guise of disease-modifying therapies that target the inflammatory and neurodegenerative components of disease have come to the forefront of preclinical research with the sole aim of reducing the underlying irreversible progressive disability of MS. Significant progress with novel therapies will be made by implementing biomarker strategies that extrapolate robustly from animal models to the divergent patient populations of MS. The future therapeutic options for MS will depend on improvements in understanding the precise factors involved in disease onset and progression and subsequently the development of oral therapeutics that translate sustained benefit from the preclinical context into clinical reality.

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Potent cyclic peptide inhibitors of VLA-4 (?4?1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-d-Arg-d-Arg) (ZD7349) compatible with depot formulation

Cited by 21 publications

References 12 publications

Comparative Assessment of the Ligand and Metal Ion Binding Properties of Integrins α9β1 and α4β1

Comparative Assessment of the Ligand and Metal Ion Binding Properties of Integrins α9β1 and α4β1

Potent Cyclic Monomeric and Dimeric Peptide Inhibitors of VLA-4 (?4?1 Integrin)-Mediated Cell Adhesion Based on the Ile-Leu-Asp-Val Tetrapeptide

Developing therapeutics for the treatment of multiple sclerosis

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