http://www.cnr.it/ontology/cnr/individuo/prodotto/ID169533
A SPR strategy for high-throughput ligand screenings based on synthetic peptides mimicking a selected subdomain of the target protein: A proof of concept on HER2 receptor (Articolo in rivista)
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- A SPR strategy for high-throughput ligand screenings based on synthetic peptides mimicking a selected subdomain of the target protein: A proof of concept on HER2 receptor (Articolo in rivista) (literal)
- Anno
- 2009-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1016/j.bmc.2009.08.004 (literal)
- Alternative label
Monfregola L.; Vitale R.M.; Amodeo P.; De Luca S. (2009)
A SPR strategy for high-throughput ligand screenings based on synthetic peptides mimicking a selected subdomain of the target protein: A proof of concept on HER2 receptor
in Bioorganic & medicinal chemistry (Print); Academic Press Ltd., Elsevier Science Ltd., London (Regno Unito)
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- Monfregola L.; Vitale R.M.; Amodeo P.; De Luca S. (literal)
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- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- a Istituto di Biostrutture e Bioimmagini IBB-CNR, 80134 Naples, Italy;
b Istituto di Chimica Biomolecolare ICB-CNR, 80078 Pozzuoli (NA), Italy (literal)
- Titolo
- A SPR strategy for high-throughput ligand screenings based on synthetic peptides mimicking a selected subdomain of the target protein: A proof of concept on HER2 receptor (literal)
- Abstract
- The discovery of pharmaceutical agents is a complex, lengthy and costly process, critically depending on
the availability of rapid and efficient screening methods. In particular, when targets are large, multidomain
proteins, their complexity may affect unfavorably technical feasibility, costs and unambiguity of
binding test interpretation.
A possible strategy to overcome these problems relies on molecular design of receptor fragments that
are: sensible targets for ligand screenings, conformationally stable also as standalone domains, easily
synthesized and immobilized on chip for Biacore experiments.
An additional desirable feature for new ligands is the ability of selectively targeting alternative conformational
states typical of many proteins.
To test the feasibility of such approach on a case with potential applicative interest, we developed a surface
plasmon resonance (SPR)-based screening method for drug candidates toward HER2, a Tyr-kinase
receptor targeted in anticancer therapies. HER2 was mimicked by HER2-DIVMP, a modified fragment
of it immobilized onto the sensor surface specifically modeling HER2 domain IV in its bounded form,
designed by structural comparison of HER2 alone and in complex with Herceptin, a monoclonal therapeutic
anti-HER2 antibody.
This design and its implementation in SPR devices was validated by investigating Herceptin- HER2-DIVMP
affinity, measuring its dissociation constant (KD = 19.2 nM). An efficient synthetic procedure to prepare
the HER2-DIVMP peptide was also developed. The HER2-DIVMP conformational stability
suggested by experimental and computational results, makes it also a valuable candidate as a mold to
design new molecules selectively targeting domain IV of HER2 (literal)
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