Design, Synthesis and Characterization of Cyclic NU172 Analogues: A Biophysical and Biological Insight.
DNA aptamers
G-quadruplex
NU172
anticoagulant activity
biophysical characterization
cyclization
duplex/quadruplex
structure-activity relationship
thrombin
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
29 May 2020
29 May 2020
Historique:
received:
06
05
2020
revised:
20
05
2020
accepted:
28
05
2020
entrez:
4
6
2020
pubmed:
4
6
2020
medline:
17
2
2021
Statut:
epublish
Résumé
NU172-a 26-mer oligonucleotide able to bind exosite I of human thrombin and inhibit its activity-was the first aptamer to reach Phase II clinical studies as an anticoagulant in heart disease treatments. With the aim of favoring its functional duplex-quadruplex conformation and thus improving its enzymatic stability, as well as its thrombin inhibitory activity, herein a focused set of cyclic NU172 analogues-obtained by connecting its 5'- and 3'-extremities with flexible linkers-was synthesized. Two different chemical approaches were exploited in the cyclization procedure, one based on the oxime ligation method and the other on Cu(I)-assisted azide-alkyne cycloaddition (CuAAC), affording NU172 analogues including circularizing linkers with different length and chemical nature. The resulting cyclic NU172 derivatives were characterized using several biophysical techniques (ultraviolet (UV) and circular dichroism (CD) spectroscopies, gel electrophoresis) and then investigated for their serum resistance and anticoagulant activity in vitro. All the cyclic NU172 analogues showed higher thermal stability and nuclease resistance compared to unmodified NU172. These favorable properties were, however, associated with reduced-even though still significant-anticoagulant activity, suggesting that the conformational constraints introduced upon cyclization were somehow detrimental for protein recognition. These results provide useful information for the design of improved analogues of NU172 and related duplex-quadruplex structures.
Identifiants
pubmed: 32485818
pii: ijms21113860
doi: 10.3390/ijms21113860
pmc: PMC7312020
pii:
doi:
Substances chimiques
Anticoagulants
0
Aptamers, Nucleotide
0
NU172
0
Oximes
0
Fibrinogen
9001-32-5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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