Bifunctional ligands that target cells displaying the alpha v beta3 integrin.

Bifunctional ligands that target cells displaying the alpha v beta3 integrin. Research Abstract Details 

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Bifunctional ligands that target cells displaying the alpha v beta3 integrin. Abstract Text:

Robert M Owen,Coby B Carlson,Jinwang Xu,Patricia Mowery,Elisabetta Fasella,Laura L Kiessling,

Strategies to eliminate tumor cells have long been sought. We envisioned that a small molecule could be used to decorate the offending cells with immunogenic carbohydrates and evoke an immune response. To this end, we describe the synthesis of bifunctional ligands possessing two functional motifs: one binds a cell-surface protein and the other binds a naturally occurring human antibody. Our conjugates combine an RGD-based peptidomimetic, to target cells displaying the alpha v beta3 integrin, with the carbohydrate antigen galactosyl-alpha(1-3)galactose [Galalpha(1-3)Gal or alpha-Gal]. To generate such bifunctional ligands, we designed and synthesized RGD mimetics 1 b and 2 c, which possess a free amino group for modification. These compounds were used to generate bifunctional derivatives 1 c and 2 d, with dimethyl squarate serving as the linchpin; thus, our synthetic approach is modular. To evaluate the binding of our peptidomimetics to the target alpha v beta3-displaying cells, we implemented a cell-adhesion assay. Results from this assay indicate that the designed, small-molecule ligands inhibit alpha v beta3-dependent cell adhesion. Additionally, our most effective bifunctional ligand exhibits a high degree of selectivity (4000-fold) for alpha v beta3 over the related alpha v beta5 integrin, a result that augurs its utility in specific cell targeting. Finally, we demonstrate that the bifunctional ligands can bind to alpha v beta3-positive cells and recruit human anti-Gal antibodies. These results indicate that both the integrin-binding and the anti-Gal-binding moieties can act simultaneously. Bifunctional conjugates of this type can facilitate the development of new methods for targeting cancer cells by exploiting endogenous antibodies. We anticipate that our modifiable alpha v beta3-binding ligands will be valuable in a variety of applications, including drug delivery and tumor targeting.

Bifunctional ligands that target cells displaying the alpha v beta3 integrin. Publishing Authors By Initials

RM Owen,CB Carlson,J Xu,P Mowery,E Fasella,LL Kiessling,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research

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Bifunctional ligands that target cells displaying the alpha v beta3 integrin. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Chembiochem : a European journal of chemical biolo

VOLUME: 8

Page Numbers: 68-82

Journal Abbreviation: Chembiochem

ISSN: 1439-4227

DAY: 2

MONTH: Jan

YEAR: 2007

Bifunctional ligands that target cells displaying the alpha v beta3 integrin. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 100937360

Bifunctional ligands that target cells displaying the alpha v beta3 integrin. Keywords Mesh Terms:

KEYWORDS: Structure-Activity Relationship

MESH TERMS: chemistry

Chemical & Substance for Abstract: Bifunctional ligands that target cells displaying the alpha v beta3 integrin. Information

Substance Name: arginyl-glycyl-aspartic acid

Registry Number: 99896-85-2

Grant and Affiliation Information for Bifunctional ligands that target cells displaying the alpha v beta3 integrin.

AFFILIATION: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

Country: Germany

AGENCY: United States NIGMS

GRANT: GM07215

ACRONYM: GM

MEDLINETA: Chembiochem

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