title: Design of Potent and Controllable Anticoagulants Using DNA Aptamers and Nanostructures.
abstract: The regulation of thrombin activity offers an opportunity to regulate blood clotting because of the central role played by this molecule in the coagulation cascade. Thrombin-binding DNA aptamers have been used to inhibit thrombin activity. In the past, to address the low efficacy reported for these aptamers during clinical trials, multiple aptamers have been linked using DNA nanostructures. Here, we modify that strategy by linking multiple copies of various thrombin-binding aptamers using DNA weave tiles. The resulting constructs have very high anticoagulant activity in functional assays owing to their improved cooperative binding affinity to thrombin due to optimized spacing, orientation, and the high local concentration of aptamers. We also report the results of molecular dynamics simulations to gain insight into the solution conformations of the tiles. Moreover, by using DNA strand displacement, we were able to turn the coagulation cascade off and on as desired, thereby enabling significantly better control over blood coagulation.
authors: Department of Materials Science and Engineering, College of Engineering, North Carolina State University, Raleigh, NC 27695, USA. abhi1jit@gmail.com.
authors: Abhijit
authors: A
authors: Rangnekar
authors: Department of Materials Science and Engineering, College of Engineering, North Carolina State University, Raleigh, NC 27695, USA. janash@ncsu.edu.
authors: Jessica A
authors: JA
authors: Nash
authors: Department of Molecular and Structural Biochemistry, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC 27695, USA. bgoodfred@gmail.com.
authors: Bethany
authors: B
authors: Goodfred
authors: Department of Materials Science and Engineering, College of Engineering, North Carolina State University, Raleigh, NC 27695, USA. yara_yingling@ncsu.edu.
authors: Yaroslava G
authors: YG
authors: Yingling
authors: Department of Materials Science and Engineering, College of Engineering, North Carolina State University, Raleigh, NC 27695, USA. thlabean@ncsu.edu.
authors: Thomas H
authors: TH
authors: LaBean
mesh_terms: D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D056004:Molecular Dynamics Simulation; D049329:Nanostructures / Q000737:chemistry*; D010314:Partial Thromboplastin Time
chemical_list: D000925:Anticoagulants; D052157:Aptamers, Nucleotide
keywords: DNA aptamers; DNA nanotechnology; anticoagulation; thrombin