This document discusses therapeutic aptamers, which are single-stranded DNA or RNA molecules that can bind to protein targets with high affinity and specificity. Aptamers are identified through a process called SELEX (Systematic Evolution of Ligands by EXponential enrichment) and can be chemically modified to improve their pharmacokinetic profiles. The document outlines the history of aptamers, the SELEX process, advantages and disadvantages of aptamers, clinical applications including the first FDA-approved aptamer Pegaptanib, and newer therapeutic targets of aptamers. Aptamers are poised to successfully compete with monoclonal antibodies in therapeutics and drug development.

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THERAPEUTIC APTAMERS
Dr.K.Sathishbabu, Final year PG, Pharmacology
25.11.2020

2. OVERVIEW
● Introduction
● History
● SELEX
● Advantages & Disadvantages
● Clinical importance
● Applications 2

3. Introduction
● Aptamers – single stranded DNA / RNA molecules that bind to
protein targets by folding into a three dimensional conformation,
similar to antibodies
● APTUS – fit ; MEROS – part or region
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4. History
● HIV – RNA has specific sequence -“Trans Activation Response (TAR)”
● TAR RNA binds with cellular/viral proteins (Cyclin T1 & Tat 
responsible for gene expression and viral replication)
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5. SELEX
● Basic principle : DNA/RNA act as ligands and that modulates target
protein activity
● Aptamers – most often isolated by a method called “SELEX”
● SELEX – Systematic Evolution of Ligands by Exponential enrichment
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6. SELEX
● Functioning mechanism :
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7. SELEX
Optimization :
● Aptamers undergo chemical modification – to modulates their
pharmacokinetic profile
● 2’ hydroxyl position – target for nuclease; To prevent degradation,
○ Fluoro modification at 2’ position of pyrimidines
○ O-methyl modification at 2’ position of purines
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8. SELEX
● Mutant T7 RNA polymerase – used to facilitate the RNA
transcription
● Addition of polyethylene glycol & cholesterol – increases half life
● Antidote oligonucleotides – avoids patient’s own clearance
mechanism
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10. ADVANTAGES
● Easier & more economical to produce aptamers
● Less toxicity & less or no immunogenicity
● Greater specificity & affinity
● More stable & reversibly denatured
● Can be easily modified chemically
● Inactivate proteins without altering genetic material
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11. DISADVANTAGES
● Aptamer identification is more expensive & labour intensive
● Variable pharmacokinetic properties
● Low affinity to some target proteins
● Unmodified aptamers are highly susceptible to serum degradation
● Short half life
● Smaller size – more prone to renal filtration
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12. CLINICAL IMPORTANCE
● Pegaptanib :
○ Only FDA approved RNA aptamer (2006)
○ Target is vascular endothelial growth factor (VEGF)
○ Used for age-related macular degeneration of the eye
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13. CLINICAL IMPORTANCE
● Pegpleranib :
○ DNA aptamer
○ Target is platelet derived
growth factor
○ Under phase II studies
● Avacinaptad pegol :
○ Modified RNA aptamer
○ Under phase II studies
● Nucleolin :
○ DNA aptamer; phase II
○ Cancer cells targeting
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14. NEWER TARGETS
● Bleeding disorders :
○ Factor IXa
○ Von williebrand factor
○ Thrombin
○ CCL2
○ Complement (C5)
● Cancer diseases :
○ Prostate-Specific Membrane
Antigen (prostate)
○ Human Epidermal Growth
Factor Receptor 2 (Breast)
○ AXL tyrosine kinase receptor
- myeloid leukemia etc. 14

15. APPLICATIONS
● New drug development
● Bio-imaging
● As therapeutic tool
● As diagnostic tool
● As drug delivery system
● Hazard detection
● Food inspection
● Drug discovery
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16. SUMMARY
● Aptamers - RNA/DNA or Protein oligonucleotide molecules
● Ability to bind to proteins with high affinity and specificity
● Can be prepared using SELEX
● Chemical modification improves pharmacokinetic profile
● Aptamers are poised to successfully compete with monoclonal Abs
in therapeutics and drug development within the next few decades.
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17. REFERENCES
● Nimjee SM, White RR, Becker RC, Sullenger BA. Aptamers as
therapeutics. Annual review of pharmacology and toxicology. 2017
Jan 6;57:61-79.
● Rusconi CP, Yeh A, Lyerly HK, Lawson JH, Sullenger BA. Blocking the
initiation of coagulation by RNA aptamers to factor VIIa Thromb.
Haemost. 2000; 84:841–48
● Achyut bora and Neelotpal sharma, Concept of aptamer and its
appliction, ppt.
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18. THANK YOU
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