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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?