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Disulfide bond replacement with non-reducible side chain to tail macrolactamization for the development of potent and selective CXCR4 peptide antagonists endowed with flanking binding sites.
Trotta, Anna Maria; Tomassi, Stefano; Di Maiolo, Gaetana; Ieranò, Caterina; Vetrei, Cinzia; D'Alterio, Crescenzo; Merlino, Francesco; Messere, Anna; D'Aniello, Antonia; Del Bene, Alessandra; Mazzarella, Vincenzo; Roggia, Michele; Natale, Benito; Cutolo, Roberto; Campagna, Erica; Mottola, Salvatore; Russo, Rosita; Chambery, Angela; Benedetti, Rosaria; Altucci, Lucia; Cosconati, Sandro; Scala, Stefania; Di Maro, Salvatore.
Afiliación
  • Trotta AM; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy.
  • Tomassi S; Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
  • Di Maiolo G; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy.
  • Ieranò C; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy.
  • Vetrei C; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy.
  • D'Alterio C; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy.
  • Merlino F; Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
  • Messere A; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • D'Aniello A; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Del Bene A; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Mazzarella V; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Roggia M; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Natale B; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Cutolo R; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Campagna E; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Mottola S; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Russo R; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Chambery A; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy.
  • Benedetti R; Department of Precision Medicine, University of Campania ''Luigi Vanvitelli'', Vico L. De Crecchio 7, 80138, Naples, Italy; Program of Medical Epigenetics, Vanvitelli Hospital, Naples, Italy.
  • Altucci L; Department of Precision Medicine, University of Campania ''Luigi Vanvitelli'', Vico L. De Crecchio 7, 80138, Naples, Italy; Program of Medical Epigenetics, Vanvitelli Hospital, Naples, Italy; Institute of Endocrinology and Oncology "Gaetano Salvatore" (IEOS), 80131, Naples, Italy; Biogem Institute o
  • Cosconati S; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy. Electronic address: sandro.cosconati@unicampania.it.
  • Scala S; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy. Electronic address: scalaste@gmail.com.
  • Di Maro S; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", 81100, Caserta, Italy. Electronic address: salvatore.dimaro@unicampania.it.
Eur J Med Chem ; 276: 116669, 2024 Oct 05.
Article en En | MEDLINE | ID: mdl-39053189
ABSTRACT
The present study describes a small library of peptides derived from a potent and selective CXCR4 antagonist (3), wherein the native disulfide bond is replaced using a side-chain to tail macrolactamization technique to vary ring size and amino acid composition. The peptides were preliminary assessed for their ability to interfere with the interaction between the receptor and anti-CXCR4 PE-conjugated antibody clone 12G5. Two promising candidates (13 and 17) were identified and further evaluated in a125I-CXCL12 competition binding assay, exhibiting IC50 in the low-nanomolar range. Furthermore, both candidates displayed high selectivity towards CXCR4 with respect to the cognate receptor CXCR7, ability to block CXCL12-dependent cancer cell migration, and receptor internalization, albeit at a higher concentration compared to 3. Molecular modeling studies on 13 and 17 produced a theoretical model that may serve as a guide for future modifications, aiding in the development of analogs with improved affinity. Finally, the study provides valuable insights into developing therapeutic agents targeting CXCR4-mediated processes, demonstrating the adaptability of our lead peptide 3 to alternative cyclization approaches and offering prospects for comprehensive investigations into the receptor region's interaction with its C-terminal region.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Receptores CXCR4 / Disulfuros Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Francia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Receptores CXCR4 / Disulfuros Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Francia