Aptamers are single-stranded oligonucleotides that fold into defined architectures and bind to targets such as proteins. In binding proteins they often inhibit protein–protein interactions and thereby may elicit therapeutic effects such as antagonism. Aptamers are discovered using SELEX (systematic evolution of ligands by exponential enrichment), a directed in vitro evolution technique in which large libraries of degenerate oligonucleotides are iteratively and alternately partitioned for target binding. They are then amplified enzymatically until functional sequences are identified by the sequencing of cloned individuals. For most therapeutic purposes, aptamers are truncated to reduce synthesis costs, modified at the sugars and capped at their termini to increase nuclease resistance, and conjugated to polyethylene glycol or another entity to reduce renal filtration rates. The first aptamer approved for a therapeutic application was pegaptanib sodium (Macugen; Pfizer/Eyetech), which was approved in 2004 by the US Food and Drug Administration for macular degeneration. Eight other aptamers are currently undergoing clinical evaluation for various haematology, oncology, ocular and inflammatory indications. Aptamers are ultimately chemically synthesized in a readily scalable process in which specific conjugation points are introduced with defined stereochemistry. Unlike some protein therapeutics, aptamers do not elicit antibodies, and because aptamers generally contain sugars modified at their 2′-positions,…
What is an Aptamer? An aptamer is a short, single-stranded oligonucleotide (DNA or RNA) or peptide that binds to a specific target molecule (e.g., proteins, small molecules, cells, viruses) with high affinity and specificity. Often called "chemical antibodies," they offer advantages like stability, low-cost synthesis, and minimal batch-to-batch variation. The Core Process: SELEX The standard method for aptamer selection is SELEX (Systematic Evolution of Ligands by EXponential enrichment). Basic SELEX Workflow: Library Synthesis: Create a vast random-sequence oligonucleotide library (typically 10¹³ - 10¹⁵ unique sequences) flanked by constant primer regions for PCR amplification. Incubation: The library is incubated with the target molecule under controlled conditions (buffer, temperature, time). Partitioning: Bound sequences are separated from unbound ones. This is the most critical step and varies based on target (e.g., filtration, affinity columns, magnetic bead separation). Elution: Bound aptamers are recovered from the target (e.g., by denaturation or competitive elution). Amplification: The recovered pool is amplified by PCR (for DNA) or RT-PCR (for RNA) to create an enriched library for the next round. Iteration: Steps 2-5 are repeated (typically 8-15 rounds) to progressively enrich for sequences with the highest affinity and specificity. Cloning & Sequencing: The final enriched pool is cloned and sequenced to identify individual aptamer candidates. Key Variants of…
The Approved Drug: Pegcetacoplan (Empaveli/Syfovre) This is actually a single aptamer molecule with two distinct FDA approvals for different diseases: Paroxysmal Nocturnal Hemoglobinuria (PNH): Approved in 2021 under the brand name Empaveli. It is a complement C3 inhibitor used to treat adults with PNH. Geographic Atrophy (GA): Approved in 2023 under the brand name Syfovre. It is used to treat GA secondary to age-related macular degeneration (AMD). How it works: Pegcetacoplan is a pegylated (attached to a polyethylene glycol chain for longer circulation) aptamer that binds specifically to complement protein C3. By inhibiting C3, it suppresses a central part of the body's complement immune system, which is overactive in both PNH and GA. Important Context and Other Notable Aptamers First-Ever Approval: The first aptamer therapeutic ever approved was Pegaptanib (Macugen) in 2004 for wet AMD. It targets VEGF. While it was a pioneering drug, it has since been largely superseded by more effective antibody-based treatments (like ranibizumab and aflibercept). It is still approved but rarely used. International Approvals: Another significant aptamer is Avacincaptad pegol (Izervay), which was also FDA-approved for Geographic Atrophy in 2023. It works by inhibiting complement C5. Aptamers in Diagnostics: While therapeutic aptamers are rare, aptamers are widely used in research and diagnostic tools. A famous example is the SOMAscan platform, which uses thousands of Slow Off-rate Modified…
