Transcript PowerPoint ****

Advance in research of aptamers
and related drugs
WANG HANLU
2015.9.6
Aptamer
 Aptamers are oligonucleotides, such as RNA and single-strand
deoxyribonucleic acid (ssDNA) or peptide molecules that can bind to
their targets with high affinity and specificity due to their specific
three-dimensional structures.
Advantages of aptamers
 Aptamers are produced chemically in a readily scalable process
 Chemical production process is not prone to viral or bacterial
contamination
 Non-immunogenic
 Smaller size allows more efficient entry into biological
compartments
Aptamers in research
The annual trends in the number of publications of aptamers-related
research. The term “aptamer” has been utilized for literature search on
Thomson Reuters Web of Science.
SELEX
(Systematic evolution of ligands by exponential enrichment)
• First reported by both Gold’s group and Szostak’s group in 1990
• SELEX experiment: a random sequence oligonucleotide library
is synthesized that spans 20–100 residues in length, and each
nucleotide is flanked by constant sequences.
• The pool will frequently contain between 1 × 1013 to 1 ×1015
members.
ELLINGTON AD，SZOSTAK JW．In vitro selection of RNA molecules that bind specific
ligands［J]. Nature，1990，346（6287）：818－822．
TUERK C，GOLD L．Systematic evolution of ligands by exponential enrichment RNA
ligands to bacteriophage-T4 DNA polymerase［J]．Science，1990，249（4968）：505－
510．
Aptamer discovery process
Various application fields of aptamers
Song, K. M. Aptamers and their biological applications. Sensors (Basel).12,
612-31(2012)
Aptamers in the Clinical Pipeline
Pegaptanib——anti-VEGF aptamer
JELLINEK D,GREEN LS,BELL C,et al. Inhibition of receptor-binding by high-affinity RNA
ligands to vascular endothelial growth-factor[J]. Biochemistry,1994,33 ( 34 ) : 10450 - 10456 .
RUCKMAN J,GREEN LS,BEESON J,et al. 2'-fluoropyrimi- dine RNA-based aptamers to the
165-amino acid form of vascular endothelial growth factor ( VEGF ( 165 ) ) -inhibition of
receptor binding and VEGF-induced vascular permeability through interac- tions requiring
the exon 7-encoded domain[J]. J Biol Chem, 1998,273( 32) : 20556 - 20567.
D‘AMICO DJ,MASONSON HN,PATEL M,et al. Pegaptanib sodium for neovascular agerelated macular degeneration-Two-year safety results of the two prospective, multicenter,
controlled clinical trials[J]. Ophthalmology,2006,113( 6) : 992 - 1001.
Optical Molecular Imaging with Aptamer-Based Probes
Schematic representation of the design of the activatable aptamers probe (AAP)
Shi H., He X., Wang K., Wu X., Ye X., Guo Q., Tan W., Qing Z., Yang X., Zhou B. Activatable
aptamer probe for contrast-enhanced in vivo cancer imaging based on cell membrane
protein-triggered conformation alteration. Proc. Natl. Acad. Sci. USA. 2011;108.
Optical Molecular Imaging with Aptamer-Based Probes
Shi H., He X., Wang K., Wu X., Ye X., Guo Q., Tan W., Qing Z., Yang X., Zhou B.
Activatable aptamer probe for contrast-enhanced in vivo cancer imaging based on
cell membrane protein-triggered conformation alteration. Proc. Natl. Acad. Sci.
USA. 2011;108.
Optical Molecular Imaging with Aptamer-Based Probes
Shi H., He X., Wang K., Wu X., Ye X., Guo Q., Tan W., Qing Z., Yang X., Zhou B.
Activatable aptamer probe for contrast-enhanced in vivo cancer imaging based on
cell membrane protein-triggered conformation alteration. Proc. Natl. Acad. Sci.
USA. 2011;108.
Aptamer-mediated drug delivery
Omid C. Farokhzad, Jianjun Cheng􏰶, Benjamin A. Teply, et al. Targeted
nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl.
Acad. Sci. USA. 2006;103.
Aptamer-mediated drug delivery
Problems
• Time-consuming in selection?
CE-SELEX, automated screening technology
• Easy to degrade in vivo?
Modified nucleoside, Capping, PEGlyation，…
• How to illustrate the binding structure?
NMR，…
• Not mature for application?