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: William M Rockey, Frank J Hernandez, Sheng-You Huang, Song Cao, Craig A Howell, Gregory S Thomas, Xiu Ying Liu, Natalia Lapteva, David M Spencer, James O McNamara, Xiaoqin Zou, Shi-Jie Chen, Paloma H Giangrande
• Journal: Nucleic acid therapeutics (Nucleic Acid Ther) Vol. 21 Issue 5 Pg. 299-314 (Oct 2011) ISSN: 2159-3345 [Electronic] United States
• PMID: 22004414 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• A9g RNA aptamer
• Aptamers, Nucleotide
• Recombinant Proteins
• Glutamate Carboxypeptidase II

Topics

• Aptamers, Nucleotide (chemistry, metabolism, pharmacology)
• Cell Line, Tumor
• Computer Simulation
• Drug Design
• Enzyme Assays
• Glutamate Carboxypeptidase II (antagonists & inhibitors, chemistry, metabolism)
• Humans
• Male
• Models, Molecular
• Nucleic Acid Conformation
• Prostatic Neoplasms
• Protein Binding
• Protein Transport
• Recombinant Proteins (chemistry, metabolism)
• Structure-Activity Relationship
• Surface Plasmon Resonance