WANG HANLU Advance in research of aptamers and related drugs

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

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. Aptamers in research

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 ． 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 × to 1 ×10 15 members.

Aptamer discovery process

Song, K. M. Aptamers and their biological applications. Sensors (Basel).12, (2012) Various application fields of aptamers

Aptamers in the Clinical Pipeline

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 ) : 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) : D‘AMICO DJ,MASONSON HN,PATEL M,et al. Pegaptanib sodium for neovascular age- related macular degeneration-Two-year safety results of the two prospective, multicenter, controlled clinical trials[J]. Ophthalmology,2006,113( 6) : Pegaptanib——anti-VEGF aptamer

Schematic representation of the design of the activatable aptamers probe (AAP) 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.

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?