Comprehensive structural investigation of a potent and selective CXCR4 antagonist via crosslink modification.

Autor: Trotta AM; Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione 'G. Pascale', 80131, Naples, Italy., Mazzarella V; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Roggia M; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., D'Aniello A; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Del Bene A; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Vetrei C; Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione 'G. Pascale', 80131, Naples, Italy., Di Maiolo G; Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione 'G. Pascale', 80131, Naples, Italy., Campagna E; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Natale B; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Rea G; Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione 'G. Pascale', 80131, Naples, Italy., Santagata S; Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione 'G. Pascale', 80131, Naples, Italy., D'Alterio C; Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione 'G. Pascale', 80131, Naples, Italy., Cutolo R; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Mottola S; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Merlino F; Department of Pharmacy, University of Naples 'Federico II', 80131, Naples, 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 of Molecular and Genetic Biology, 83031, Ariano Irpino, Italy., Messere A; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Cosconati S; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', Via A. Vivaldi, 43, 81100, Caserta, Italy., Tomassi S; Department of Life Science, Health, and Health Professions, LINK Campus University, Via del Casale di San Pio V, 44, 00165, Rome, Italy. Electronic address: s.tomassi@unilink.it., Scala S; Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei 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', Via A. Vivaldi, 43, 81100, Caserta, Italy. Electronic address: salvatore.dimaro@unicampania.it.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 05; Vol. 279, pp. 116911. Date of Electronic Publication: 2024 Sep 25.
DOI: 10.1016/j.ejmech.2024.116911
Abstrakt: Macrocyclization presents a valuable strategy for enhancing the pharmacokinetic and pharmacodynamic profiles of short bioactive peptides. The exploration of various macrocyclic characteristics, such as crosslinking tethers, ring size, and orientation, is generally conducted during the early stages of development. Herein, starting from a potent and selective C-X-C chemokine receptor 4 (CXCR4) cyclic heptapeptide antagonist mimicking the N-terminal region of CXCL12, we demonstrated that the disulfide bridge could be successfully replaced with a side-chain to side-chain lactam bond, which is commonly not enlisted among the conventional disulfide mimetics. An extensive investigation was carried out to explore the chemical space of the resulting peptides, including macrocyclization width, stereochemical configuration, and lactam orientation, all of which were correlated with biochemical activity. We identified a novel heptapeptide that fully replicates the pharmacological profile of the parent peptide on CXCR4, including its potency, selectivity, and antagonistic activity, while demonstrating enhanced stability in a reductive environment. At this stage, computational studies were instructed to shed light on how the lactam cyclization features influenced the overall structure of 21 and, in turn, its ability to interact with the receptor. We envisage that these findings can give new momentum to the use of lactam cyclization as a disulfide bond mimetic and contribute to the enhancement of the repertoire for peptide-based drug development, thereby paving the way for novel avenues in therapeutic innovation.
Competing Interests: Declaration of competing interest On behalf of all the authors of the manuscript titled "Comprehensive Structural Investigation of a Potent and Selective CXCR4 Antagonist via Crosslink Modification" I confirm that A. M. T. and S. S. declare a conflict of interest as they hold a patent on one of the compounds mentioned in the article (compound 1) (WO2021130329A1). The remaining authors have no conflicts of interest to declare.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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