Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle.
Animals
Blood Proteins
/ metabolism
CD36 Antigens
/ genetics
Caveolin 3
/ genetics
Fatty Acids
/ chemistry
Fatty Acids, Unsaturated
/ chemistry
Male
Mice, Inbred C57BL
Muscle, Skeletal
/ metabolism
Myocardium
/ metabolism
Myotonin-Protein Kinase
/ genetics
Oligonucleotides, Antisense
/ chemical synthesis
Palmitic Acid
/ chemistry
RNA, Long Noncoding
/ metabolism
Structure-Activity Relationship
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
09 07 2019
09 07 2019
Historique:
accepted:
26
04
2019
revised:
19
04
2019
received:
22
03
2019
pubmed:
28
5
2019
medline:
26
2
2020
entrez:
26
5
2019
Statut:
ppublish
Résumé
Enhancing the functional uptake of antisense oligonucleotide (ASO) in the muscle will be beneficial for developing ASO therapeutics targeting genes expressed in the muscle. We hypothesized that improving albumin binding will facilitate traversal of ASO from the blood compartment to the interstitium of the muscle tissues to enhance ASO functional uptake. We synthesized structurally diverse saturated and unsaturated fatty acid conjugated ASOs with a range of hydrophobicity. The binding affinity of ASO fatty acid conjugates to plasma proteins improved with fatty acid chain length and highest binding affinity was observed with ASO conjugates containing fatty acid chain length from 16 to 22 carbons. The degree of unsaturation or conformation of double bond appears to have no influence on protein binding or activity of ASO fatty acid conjugates. Activity of fatty acid ASO conjugates correlated with the affinity to albumin and the tightest albumin binder exhibited the highest activity improvement in muscle. Palmitic acid conjugation increases ASO plasma Cmax and improved delivery of ASO to interstitial space of mouse muscle. Conjugation of palmitic acid improved potency of DMPK, Cav3, CD36 and Malat-1 ASOs (3- to 7-fold) in mouse muscle. Our approach provides a foundation for developing more effective therapeutic ASOs for muscle disorders.
Identifiants
pubmed: 31127296
pii: 5498623
doi: 10.1093/nar/gkz354
pmc: PMC6614804
doi:
Substances chimiques
Blood Proteins
0
CD36 Antigens
0
Cav3 protein, mouse
0
Caveolin 3
0
DMPK protein, mouse
0
Fatty Acids
0
Fatty Acids, Unsaturated
0
Malat1 long non-coding RNA, mouse
0
Oligonucleotides, Antisense
0
RNA, Long Noncoding
0
Palmitic Acid
2V16EO95H1
Myotonin-Protein Kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6029-6044Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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