Cellular Uptake and Cytosolic Delivery of a Cyclic Cystine Knot Scaffold.
Journal
ACS chemical biology
ISSN: 1554-8937
Titre abrégé: ACS Chem Biol
Pays: United States
ID NLM: 101282906
Informations de publication
Date de publication:
19 06 2020
19 06 2020
Historique:
pubmed:
22
4
2020
medline:
27
4
2021
entrez:
22
4
2020
Statut:
ppublish
Résumé
Cyclotides are macrocyclic peptides with exceptionally stable structures and have been reported to penetrate cells, making them promising scaffolds for the delivery of inhibitory peptides to target intracellular proteins. However, their cellular uptake and cytosolic localization have been poorly understood until now, which has limited their therapeutic potential. In this study, the recently developed chloroalkane penetration assay was combined with established assays to characterize the cellular uptake and cytosolic delivery of the prototypic cyclotide, kalata B1. We show that kalata B1 enters the cytosol at low efficiency. A structure-activity study of residues in loop 6 showed that some modifications, such as increasing cationic residue content, did not affect delivery efficiency, whereas others, including introducing a single hydrophobic amino acid, did significantly improve cytosolic delivery. Our results provide a foundation for the further development of a structurally unique class of scaffolds for the delivery of therapeutic cargoes into cells.
Identifiants
pubmed: 32315152
doi: 10.1021/acschembio.0c00297
pmc: PMC7831380
mid: NIHMS1662879
doi:
Substances chimiques
Cyclotides
0
Fluorescent Dyes
0
kalata B1
0
Cystine
48TCX9A1VT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1650-1661Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM127585
Pays : United States
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