In addition to classic small-molecule drugs and modern protein-based biologics, an intriguing class of medicines is the therapeutic oligonucleotides. Most approved drugs in this category are antisense oligomers or those acting via RNA interference, both of which use base hybridization. Aptamers, also known as chemical antibodies form a smaller, yet equally interesting group of oligonucleotides that can recognize a wide range of molecular targets. Despite their high potential, only two aptamers have been approved to date, pegaptanib (MacugenTM) and avacincaptad pegol (IzervayTM), both for the treatment of age-related macular degeneration (AMD). Targeting vascular endothelial growth factor (VEGF), which plays an important role in the pathogenesis of many eye diseases, pegaptanib emerged as the first anti-VEGF agent and was used in various indications, further inspiring the development of other anti-VEGF therapies. In this review, we summarize the history of the first approved aptamer medicine, pegaptanib. We describe its chemistry and track its development from the earliest stages to the preclinical phase, clinical trials, and eventual regulatory approval. Additionally, we evaluate its position among other therapeutic agents and provide a comprehensive overview of pegaptanib’s efficacy, safety, and cost-effectiveness, comparing these aspects with those of monoclonal antibodies with similar indications, bevacizumab and ranibizumab.

Background: Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic phytocannabinoids that have significant, broad-spectrum therapeutic potential in a variety of pharmacological areas, but their unfavorable pharmacokinetics, such as extensive first-pass metabolism and low bioavailability, hinder their effective medical applications. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical properties. Incorporation of fluorine atom(s) at appropriate positions often improves the metabolic stability of the parent compound, increasing its bioavailability, and enhances its binding affinity to therapeutic targets, making fluorine a highly valuable element in modern drug development. Furthermore, amino functional groups may improve the water solubility and bioavailability of the compounds. Building on these principles, our strategy focused on introducing groups containing mono-, di-, and trifluoroethylamine or fluorinated aniline moieties into cannabinoids to improve their pharmacokinetic and pharmacological profiles. Methods: Mannich-type reaction was applied, using commercially available 2-fluoroethylamine, 2,2-difluoroethylamine, 2,2,2-trifluoroethylamine, 3-fluoroaniline and 4-fluoroaniline as reagents. One or two oxazine rings with fluorine-containing side chains were condensed to the aromatic core of the cannabinoids, and the formation of mono- or disubstituted derivatives was controlled by the appropriate choice of reaction conditions. The biological activity of the derivatives was investigated in various relevant fields. Results and conclusion: Our findings indicate that aliphatic modifications positively influence pharmacokinetic parameters, including absorption, in contrast to aromatic groups, which increase lipophilicity and lead to decreased bioavailability. Among the modifications, the monosubstituted derivatives containing a single oxazine ring with an aliphatic fluorine-containing side chain, especially the mono- and trifluoroethyl moieties, proved to be the most promising. These modifications appeared particularly advantageous in the CBG series compared to the properties of the CBG parent compound. This may suggest that the presence of a phenolic OH group is beneficial for biological activity. Some of the derivatives showed anticancer potential against various tumor cell lines, while others modulated sebaceous lipogenesis, and certain compounds exhibited a notable antimalarial effect.

Therapeutic oligonucleotides are employed in the treatment of a variety of diseases, primarily functioning through mechanisms associated with gene silencing technologies. In contrast, aptamers exhibit mechanisms of action that are more akin to those of protein-based monoclonal antibodies. However, owing to their oligonucleotide structure, aptamers possess several advantages over antibodies. Despite these benefits, the adoption of aptamers in clinical medicine has not reached the levels observed with monoclonal antibodies or gene-silencing oligonucleotides. Almost two decades after the approval of pegaptanib, the first approved aptameric therapeutic for the treatment of neovascular AMD (age-related macular degeneration), a second aptamer has recently received approval to treat geographic atrophy, an advanced form of AMD. In this review, we aim to provide an overview of the pharmacology and chemistry of avacincaptad pegol, the second approved aptameric drug.

Morpholino nucleosides play an important role in medicine as building blocks for antisense oligonucleotide drugs (PMOs), but their therapeutic applications as nucleosides are still unexplored. A novel library of 38 fused bicyclic morpholino-uridine and -adenosine derivatives was constructed through an innovative, single-step strategy based on a reductive aminocyclization reaction between readily prepared nucleoside secodialdehydes and bifunctional amines. By fine-tuning the reaction conditions, a diverse array of morpholino bicycles was obtained with high/complete stereoselectivity. With aminothiols and diamines, the NaCNBH3–AcOH reducing agent resulted in 3′-fused or 5′-fused ring systems, depending on the amine reactant, while the NaCNBH3–ZnCl2-mediated reduction gave predominantly 5′-fused bicycles due to intramolecular 3′-hydride donation by the reducing agent coordinated to the nucleobase. All new compounds were evaluated for their antiviral activity against SARS-CoV-2. Three analogues demonstrated significant efficacy, exhibiting single-digit micromolar EC50 values. Mechanistic investigations revealed that these compounds inhibit the viral life cycle at a postentry stage, with one compound potentially affecting later stages of the viral replication cycle. Furthermore, molecular docking, enzymatic inhibition studies, and in silico ADMET analyses were conducted. The findings emphasize the potential of this fused bicyclic system as an attractive scaffold in nucleoside chemistry and advocate for its further optimization as a promising class of SARS-CoV-2 inhibitors.