Design and synthesis of a bivalent probe targeting the putative mu opioid receptor and chemokine receptor CXCR4 heterodimer.
Journal
RSC medicinal chemistry
ISSN: 2632-8682
Titre abrégé: RSC Med Chem
Pays: England
ID NLM: 101759460
Informations de publication
Date de publication:
01 Jan 2020
01 Jan 2020
Historique:
received:
10
09
2019
accepted:
18
10
2019
entrez:
22
1
2021
pubmed:
19
12
2019
medline:
19
12
2019
Statut:
epublish
Résumé
Opioid abuse and HIV/AIDS have been defined as synergistic epidemics. Opioids can accelerate HIV replication in the immune system by up-regulating the expression of HIV co-receptor CXCR4. Several hypotheses have been suggested as the mechanism of CXCR4 modulation by opioids through their activation on the mu opioid receptor (MOR). One hypothesis is the putative heterodimerization of the MOR and CXCR4 as a mechanism of cross-talk and subsequent exacerbation of HIV replication. Bivalent chemical probes can be powerful molecular tools to characterize protein-protein interactions, and modulate the function related to such interactions. Herein we report the design and synthesis of a novel bivalent probe to explore the putative MOR-CXCR4 dimerization and its potential pharmacological role in enhancing HIV progression. The developed bivalent probe was designed with two distinct pharmacophores linked through a spacer. One pharmacophore (naltrexone) will interact with the MOR and the other (IT1t) with the CXCR4. The overall synthetic routes to prepare the bivalent probe and its corresponding monovalent controls were comprised of 18-22 steps with acceptable yields. Preliminary biological evaluation showed that the bivalent probe preserved binding affinity and functional activity at both respective receptors, supporting the initial molecular design.
Identifiants
pubmed: 33479612
doi: 10.1039/c9md00433e
pii: c9md00433e
pmc: PMC7451026
doi:
Types de publication
Journal Article
Langues
eng
Pagination
125-131Subventions
Organisme : NIDA NIH HHS
ID : R01 DA044855
Pays : United States
Organisme : NIMH NIH HHS
ID : R25 MH080661
Pays : United States
Organisme : NIDA NIH HHS
ID : T32 DA007027
Pays : United States
Informations de copyright
This journal is © The Royal Society of Chemistry 2020.
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