Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors

A mutant of echistatin, a disintegrin with a high affinity for the integrins, was constructed by substituting CRGDC for ARGDIJ in the Arg-Gly-Asp (RGD) region. The mutant was chemically synthesized, subjected to a folding process with air oxidation, and purified by reverse-phase HPLC. The peptide mapping and mass spectrometric analyses revealed that the two Cys residues introduced in the mutant are linked to each other, without any effect on the mode of the four disultide bonds present in native ecblstatin, as expected. The mutant strongly inhibited the binding of human fibrinogen to its receptor, integrin aIn,p3, with an I&, value of 0.12 nM. This value shows that the mutant is twice as potent as the native form (IQ, = 0.23 &I). These results indicate that the native disintegrin molecule, which has been considered to possess the optimum affinity for the integrins, can be tailored to exhibit even higher affinity by introducing the conformational constraint into the RGD region. Monte Carlo simulations of KRCRGDCMD, the RGD region in the mutant, suggested that the disulfide bond constrains the RGD region to assume a type II' p-turn, with Gly and Asp in positions 2 and 3 of the turn.

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“…This speculation agrees with the idea that the integrin an& contains an unrecognized exosite other than the RGD binding site [20].…”

Section: Discussionsupporting

confidence: 90%

Tailoring echistatin to possess higher affinity for integrin α_IIbβ₃

Yamada

Kidera

1996

FEBS Letters

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“…This scaffold was initially considered by the Merck group for the research of platelet receptor R IIb β 3 antagonists, 78 giving tirofibane as cardiovascular drug, and more recently used by Kessler et al for the design of selective R 5 β 1 ligands, 42,52 potentially useful in the field of antiangiogenic cancer therapy. Both receptors, R IIb β 3 and R 5 β 1 feature high sequence similarity with R v β 3 integrin.…”

Section: Resultsmentioning

confidence: 99%

α_vβ₃ Integrin-Targeting Arg-Gly-Asp (RGD) Peptidomimetics Containing Oligoethylene Glycol (OEG) Spacers

et al. 2009

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RGD peptides are used in biomaterials science for surface modifications with a view to elicit selective cellular responses. Our objective is to replace peptides by small peptidomimetics acting similarly. We designed novel molecules targeting R v β 3 integrin and featuring spacer-arms (for surface grafting), which do not disturb the biological activity, from (L) N-(3-(trifluoromethyl)benzenesulfonyl) tyrosine used as scaffold. Various Arg-mimics were fixed on the phenol function, and the ortho position was used for the coupling of OEG spacers. All peptidomimetics were active in the nM range in a binding test toward human R v β 3 integrin (IC 50 = 0.1 to 1.7 nM) and selective versus platelet integrin R IIb β 3 . Selected compounds revealed excellent ability to inhibit bone cells adhesion on vitronectin. Modeling and docking studies were performed for comparing the most active RGD peptidomimetic to cilengitide, i.e., cyclo-[RGDfN(Me)V]-. Lastly, the adhesion of endothelial cells on a cultivation support grafted with RGD peptidomimetics was significantly improved.

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“…175, No. 4 molecules or therapeutic antibodies have relative merits based on bioavailability, route of administration, half-life, specificity, and toxicity, and there are currently Food and Drug Administration-approved examples of each being used as anti-integrin ␣IIb␤IIIa antiplatelet agents (tirofiban 103 and abciximab, 104 respectively). Other therapeutic monoclonal anti-integrin antibodies have been developed or are in various phases of preclinical testing.…”

Section: Tgf-␤ Activation In Fibrogenic Disorders 1367mentioning

confidence: 99%

Integrin-Mediated Transforming Growth Factor-β Activation, a Potential Therapeutic Target in Fibrogenic Disorders

Nishimura

2009

The American Journal of Pathology

133

122

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Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors

Cited by 282 publications

References 1 publication

Tailoring echistatin to possess higher affinity for integrin α_IIbβ₃

Tailoring echistatin to possess higher affinity for integrin α_IIbβ₃

α_vβ₃ Integrin-Targeting Arg-Gly-Asp (RGD) Peptidomimetics Containing Oligoethylene Glycol (OEG) Spacers

Integrin-Mediated Transforming Growth Factor-β Activation, a Potential Therapeutic Target in Fibrogenic Disorders

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Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors

Cited by 282 publications

References 1 publication

Tailoring echistatin to possess higher affinity for integrin αIIbβ3

Tailoring echistatin to possess higher affinity for integrin αIIbβ3

αvβ3 Integrin-Targeting Arg-Gly-Asp (RGD) Peptidomimetics Containing Oligoethylene Glycol (OEG) Spacers

Integrin-Mediated Transforming Growth Factor-β Activation, a Potential Therapeutic Target in Fibrogenic Disorders

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Product

Resources

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Tailoring echistatin to possess higher affinity for integrin α_IIbβ₃

Tailoring echistatin to possess higher affinity for integrin α_IIbβ₃

α_vβ₃ Integrin-Targeting Arg-Gly-Asp (RGD) Peptidomimetics Containing Oligoethylene Glycol (OEG) Spacers