Reversible regulation of aptamer activity with effector-responsive hairpin oligonucleotides.
Aptamers are oligonucleotides that can bind to various nonnucleic acid molecular targets in a high affinity and specificity. As an emerging class of therapeutic agents, aptamers offer an unparalleled advantage over other classes of therapeutic agents: the possibility to rationally regulate the therapeutic activity of aptamers. Most existing strategies for regulating the aptamer activity have a limited specificity and/or reversibility. Herein we report a simple, generic strategy to simultaneously achieve specificity and reversibility by exploiting the spontaneous conformational change of hairpin oligonucleotides upon the specific recognition of nucleic acid effectors. The effector-responsive hairpin oligonucleotide consists of a sensing loop that recognizes a particular nucleic acid effector, an aptamer stem that inhibits a certain therapeutic target, and an antidote stem that is complementary to the aptamer. Upon the introduction/removal of the effector, the hairpin oligonucleotide undergoes a conformational change that activates/deactivates the aptamer's inhibiting activity on the therapeutic target. This new strategy has been demonstrated with an anticoagulant aptamer that binds and inhibits human α-thrombin.
Department of Mechanical & Aerospace Engineering, University of Miami, Coral Gables, FL 33146, USA. n.li1@miami.edu
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D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000494:pharmacology*; D001483:Base Sequence; D001777:Blood Coagulation / Q000187:drug effects; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011485:Protein Binding / Q000187:drug effects; D012996:Solutions; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism
D052157:Aptamers, Nucleotide; D012996:Solutions; D005340:Fibrinogen; D013917:Thrombin