Targeting the X-Linked Inhibitor of Apoptosis Protein through 4-Substituted Azabicyclo[5.3.0]alkane Smac Mimetics. Structure, Activity, and Recognition Principles (Articolo in rivista)

Type

• Articolo in rivista (Classe)
• Prodotto della ricerca (Classe)

Label

• Targeting the X-Linked Inhibitor of Apoptosis Protein through 4-Substituted Azabicyclo[5.3.0]alkane Smac Mimetics. Structure, Activity, and Recognition Principles (Articolo in rivista) (literal)

Anno

• 2008-01-01T00:00:00+01:00 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi

• 10.1016/j.jmb.2008.09.064 (literal)

Alternative label

• Mastrangelo, E.; Cossu, F.; Milani, M.; Sorrentino, G.; Lecis, D.; Delia, D.; Manzoni, L.; Drago, C.; Seneci, P.; Scolastico C.; Rizzo, V.; Bolognesi, M. (2008)
  Targeting the X-Linked Inhibitor of Apoptosis Protein through 4-Substituted Azabicyclo[5.3.0]alkane Smac Mimetics. Structure, Activity, and Recognition Principles
  in Journal of Molecular Biology
  (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

• Mastrangelo, E.; Cossu, F.; Milani, M.; Sorrentino, G.; Lecis, D.; Delia, D.; Manzoni, L.; Drago, C.; Seneci, P.; Scolastico C.; Rizzo, V.; Bolognesi, M. (literal)

Pagina inizio

• 673 (literal)

Pagina fine

• 689 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume

• 384 (literal)

Rivista

• Journal of Molecular Biology (Rivista)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#note

• DOI:10.1016/j.jmb.2008.09.064 (literal)

Note

• ISI Web of Science (WOS) (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

• \"[Mastrangelo, Eloise; Cossu, Federica; Milani, Mario; Sorrentino, Graziella; Bolognesi, Martino] Univ Milan, Dept Biomol Sci & Biotechnol, CNR, INFM, I-20133 Milan, Italy; [Mastrangelo, Eloise; Cossu, Federica; Milani, Mario; Sorrentino, Graziella; Bolognesi, Martino] Univ Milan, CIMAINA, I-20133 Milan, Italy; [Lecis, Daniele; Delia, Domenico] Ist Nazl Tumori, I-20133 Milan, Italy; [Manzoni, Leonardo] CNR, Ist Sci & Tecnol Mol, I-20138 Milan, Italy; [Cossu, Federica; Drago, Carmelo Seneci, Pierfausto; Scolastico, Carlo; Rizzo, Vincenzo] Univ Milan, Ctr Interdisciplinare Biomol & Applicaz Ind, I-20138 Milan, Italy; [Seneci, Pierfausto; Scolastico, Carlo] Univ Milan, Dept Organ & Ind Chem, I-20133 Milan, Italy (literal)

Titolo

• Targeting the X-Linked Inhibitor of Apoptosis Protein through 4-Substituted Azabicyclo[5.3.0]alkane Smac Mimetics. Structure, Activity, and Recognition Principles (literal)

Abstract

• The X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in several malignant cells where it prevents apoptosis by binding to, and blocking, the activation of caspase-3,-7, and -9. Human XIAP (479 residues) is composed of three tandem-repeated baculoviral TAP repeat (BIR) domains (BIR1-3), and by a C-terminal RING domain. Smac-DIABLO [second mitochondria -derived activator of caspases (Smac)-direct TAP binding protein with low PI (DIABLO)], the natural antagonist of XIAP, binds through its N-terminal, sequence AVPI to the same surface groove, in the BIR domains, that binds caspases. Synthetic compounds mimicking such tetrapeptide motif effectively block the interaction between TAP and active caspases, thus triggering apoptosis. Peptidomimetics based on an azabicyclo[x.y.0]alkane scaffolds, have been shown to bind the BIR3 domain of XIAP with micromolar to nanomolar affinities, thus presenting attractive features for drug lead optimization. Here we report a study on three newly synthesized Smac mimetics, which have been characterized in their complexes with XIAP BIR3 domain through X-ray crystallography and molecular modelling/ docking simulations. Based on analysis of the crystal structures, we show that specific substitutions at the 4-position of the azabicyclo[5.3.0]alkane scaffold results in sizeable effects on the peptidomitnetic-BIR3 domain affinity. By means of functional, biophysical and simulative approaches we also propose that the same Smac mimetics can bind XIAP BIR2 domain at a location structurally related to the BIR3 domain AVPI binding groove. Details of the XIAP-Smac mimetic recognition principles highlighted by this study are discussed in light of the drug-like profile of the three (potentially proapoptotic) compounds developed that show improved performance in ADMET (adsorption, distribution, metabolism, excretion and toxicity) tests. (literal)

Prodotto di

• Istituto di scienze e tecnologie molecolari (ISTM) (Istituto)
• Generazione di radiazione X ultrabeve (MD.P03.007.001) (Modulo)
• Produzione di (PM.P06.012.001) (Modulo)

Autore CNR

• LEONARDO PIERPAOLO MANZONI (Unità di personale interno)
• ELOISE MASTRANGELO (Unità di personale interno)
• MARIO MILANI DE MAYO DE MARI (Unità di personale interno)

Insieme di parole chiave

• Keywords of "Targeting the X-Linked Inhibitor of Apoptosis Protein through 4-Substituted Azabicyclo[5.3.0]alkane Smac Mimetics. Structure, Activity, and Recognition Principles" (Insieme di parole chiave)

Incoming links:

Prodotto

• Istituto di scienze e tecnologie molecolari (ISTM) (Istituto)
• Generazione di radiazione X ultrabeve (MD.P03.007.001) (Modulo)
• Produzione di (PM.P06.012.001) (Modulo)

Autore CNR di

• LEONARDO PIERPAOLO MANZONI (Unità di personale interno)
• ELOISE MASTRANGELO (Unità di personale interno)
• MARIO MILANI DE MAYO DE MARI (Unità di personale interno)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#rivistaDi

• Journal of Molecular Biology (Rivista)

Insieme di parole chiave di

• Keywords of "Targeting the X-Linked Inhibitor of Apoptosis Protein through 4-Substituted Azabicyclo[5.3.0]alkane Smac Mimetics. Structure, Activity, and Recognition Principles" (Insieme di parole chiave)