title: Structural computational modeling of RNA aptamers.
abstract: RNA aptamers represent an emerging class of biologics that can be easily adapted for personalized and precision medicine. Several therapeutic aptamers with desirable binding and functional properties have been developed and evaluated in preclinical studies over the past 25years. However, for the majority of these aptamers, their clinical potential has yet to be realized. A significant hurdle to the clinical adoption of this novel class of biologicals is the limited information on their secondary and tertiary structure. Knowledge of the RNA's structure would greatly facilitate and expedite the post-selection optimization steps required for translation, including truncation (to reduce costs of manufacturing), chemical modification (to enhance stability and improve safety) and chemical conjugation (to improve drug properties for combinatorial therapy). Here we describe a structural computational modeling methodology that when coupled to a standard functional assay, can be used to determine key sequence and structural motifs of an RNA aptamer. We applied this methodology to enable the truncation of an aptamer to prostate specific membrane antigen (PSMA) with great potential for targeted therapy that had failed previous truncation attempts. This methodology can be easily applied to optimize other aptamers with therapeutic potential.
authors.affiliation: Department of Physics, Department of Biochemistry, and Informatics Institute, University of Missouri-Columbia, Columbia, MO 65211, United States.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, University of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA 52242, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Dickey
authors.affiliation: Department of Physics, Department of Biochemistry, and Informatics Institute, University of Missouri-Columbia, Columbia, MO 65211, United States. Electronic address: ChenShi@missouri.edu.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA 52242, United States. Electronic address: paloma-giangrande@uiowa.edu.
authors.forename: Paloma H
authors.initials: PH
authors.lastname: Giangrande
mesh_terms: D052157:Aptamers, Nucleotide / Q000737:chemistry*; D003198:Computer Simulation; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry; D006801:Humans; D055029:Inverted Repeat Sequences; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D052156:SELEX Aptamer Technique; D012984:Software
chemical_list: D052157:Aptamers, Nucleotide; D043425:Glutamate Carboxypeptidase II
keywords: A9 aptamer; A9g aptamer; NAALADase Assay; Prostate specific membrane antigen (PSMA); RNA aptamers; RNA secondary and tertiary structure; Structural algorithms; Vfold2D model; Vfold3D model