Rational truncation of an RNA aptamer to prostate-specific membrane antigen using computational structural modeling.
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 +12 more
TLDR
This work substantially truncates A9, an RNA aptamer to prostate-specific membrane antigen (PSMA), which retains binding activity, functionality, and is amenable to large-scale chemical synthesis for future clinical applications and 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.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.read more
Citations
More filters
Journal ArticleDOI
Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression
Fengmei Pi,Daniel W. Binzel,Tae Jin Lee,Tae Jin Lee,Zhefeng Li,Meiyan Sun,Piotr G. Rychahou,Hui Li,Farzin Haque,Shaoying Wang,Carlo M. Croce,Bin Guo,B. Mark Evers,Peixuan Guo +13 more
TL;DR: The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA) in cancer treatment.
Journal ArticleDOI
Advancement of the Emerging Field of RNA Nanotechnology.
TL;DR: This review aims to outline the current state of the art of RNA nanoparticles as programmable smart complexes and offers perspectives on the promising avenues of research in this fast-growing field.
Journal ArticleDOI
Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference-based bone anabolic strategy.
Chao Liang,Baosheng Guo,Heng Wu,Ningsheng Shao,Defang Li,Jin Liu,Lei Dang,Cheng Wang,Hui Li,Shaohua Li,Wing Ki Lau,Yu Cao,Zhijun Yang,Cheng Lu,Xiaojuan He,Doris W.T. Au,Xiaohua Pan,Bao-Ting Zhang,Changwei Lu,Hong Qi Zhang,Kinman Yue,Airong Qian,Peng Shang,Jiake Xu,Lianbo Xiao,Zhaoxiang Bian,Weihong Tan,Zicai Liang,Fuchu He,Lingqiang Zhang,Aiping Lu,Ge Zhang +31 more
TL;DR: The results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.
Journal ArticleDOI
Targeting Axl With an High-affinity Inhibitory Aptamer
Laura Cerchia,Carla Lucia Esposito,Simona Camorani,Anna Rienzo,Loredana Stasio,Luigi Insabato,Andrea Affuso,Vittorio de Franciscis +7 more
TL;DR: The generated and characterized a selective RNA-based aptamer, GL21.T, that binds the extracellular domain of Axl at high affinity and inhibits its catalytic activity and represents a promising therapeutic molecule for Axl-dependent cancers whose importance is highlighted by the paucity of availableAxl-specific inhibitory molecules.
Journal ArticleDOI
Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma.
Chao Liang,Fangfei Li,Luyao Wang,Zong-Kang Zhang,Chao Wang,Bing He,Jie Li,Zhihao Chen,Atik Badshah Shaikh,Jin Liu,Xiaohao Wu,Songlin Peng,Lei Dang,Baosheng Guo,Xiaojuan He,Doris W.T. Au,Cheng Lu,Hailong Zhu,Bao-Ting Zhang,Aiping Lu,Ge Zhang +20 more
TL;DR: This work screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9, leading to effective VEG FA genome editing in tumor and reduced angiogenesis and bone lesion with no detectable toxicity.
References
More filters
Journal ArticleDOI
In vitro selection of RNA molecules that bind specific ligands.
TL;DR: Subpopulations of RNA molecules that bind specifically to a variety of organic dyes have been isolated from a population of random sequence RNA molecules.
Journal ArticleDOI
The Amber biomolecular simulation programs
David A. Case,Thomas E. Cheatham,Tom Darden,Holger Gohlke,Ray Luo,Kenneth M. Merz,Alexey V. Onufriev,Carlos Simmerling,Bing Wang,Robert J. Woods +9 more
TL;DR: The development, current features, and some directions for future development of the Amber package of computer programs, which contains a group of programs embodying a number of powerful tools of modern computational chemistry, focused on molecular dynamics and free energy calculations of proteins, nucleic acids, and carbohydrates.
Journal ArticleDOI
Pegaptanib for Neovascular Age-Related Macular Degeneration
TL;DR: Pegaptanib, an anti-vascular endothelial growth factor therapy, was evaluated in the treatment of neovascular age-related macular degeneration.
Journal ArticleDOI
Aptamers as therapeutics.
TL;DR: A series of aptamers currently in development may change how nucleic acid therapeutics are perceived and will increasingly find use in concert with other therapeutic molecules and modalities.
Journal Article
Prostate-specific membrane antigen expression in normal and malignant human tissues.
TL;DR: The decrease in PSMA immunoreactivity noted in advanced prostate cancer suggests that expression of this molecule may be linked to the degree of tumor differentiation and the neoexpression of PSMA in endothelial cells of capillary beds in certain tumors may be related to tumor angiogenesis and suggests a potential mechanism for specific targeting of tumor neovasculature.
Related Papers (5)
Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase
Craig Tuerk,Larry Gold +1 more