title: Rational truncation of an RNA aptamer to prostate-specific membrane antigen using computational structural modeling.
abstract: RNA aptamers represent an emerging class of pharmaceuticals with great potential for targeted cancer diagnostics and therapy. Several RNA aptamers that bind cancer cell-surface antigens with high affinity and specificity have been described. However, their clinical potential has yet to be realized. A significant obstacle to the clinical adoption of RNA aptamers is the high cost of manufacturing long RNA sequences through chemical synthesis. Therapeutic aptamers are often truncated postselection by using a trial-and-error process, which is time consuming and inefficient. Here, we used a "rational truncation" approach guided by RNA structural prediction and protein/RNA docking algorithms that enabled us to substantially truncateA9, an RNA aptamer to prostate-specific membrane antigen (PSMA),with great potential for targeted therapeutics. This truncated PSMA aptamer (A9L; 41mer) retains binding activity, functionality, and is amenable to large-scale chemical synthesis for future clinical applications. In addition, the modeled RNA tertiary structure and protein/RNA docking predictions revealed key nucleotides within the aptamer critical for binding to PSMA and inhibiting its enzymatic activity. Finally, this work highlights the utility of existing RNA structural prediction and protein docking techniques that may be generally applicable to developing RNA aptamers optimized for therapeutic use.
authors: Department of Radiation Oncology, University of Iowa, Iowa City, USA.
authors: William M
authors: WM
authors: Rockey
authors: Frank J
authors: FJ
authors: Hernandez
authors: Sheng-You
authors: SY
authors: Huang
authors: Song
authors: S
authors: Cao
authors: Craig A
authors: CA
authors: Howell
authors: Gregory S
authors: GS
authors: Thomas
authors: Xiu Ying
authors: XY
authors: Liu
authors: Natalia
authors: N
authors: Lapteva
authors: David M
authors: DM
authors: Spencer
authors: James O
authors: JO
authors: McNamara
authors: Xiaoqin
authors: X
authors: Zou
authors: Shi-Jie
authors: SJ
authors: Chen
authors: Paloma H
authors: PH
authors: Giangrande
mesh_terms: D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D057075:Enzyme Assays; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011471:Prostatic Neoplasms; D011485:Protein Binding; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: C000602292:A9g RNA aptamer; D052157:Aptamers, Nucleotide; D011994:Recombinant Proteins; D043425:Glutamate Carboxypeptidase II