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Applications of aptamers as GPCR targeting drugs

The current wave of COVID-19 infections around the globe has resulted from a novel coronavirus employing its spike glycoprotein to bind with the protein binding sites of the host cells. These virus particles have the notorious tendency to proteolytically generate mutated biologically active fragments involved in signal transduction pathway resulting in the proliferation and transmission of viral cells.

G-protein-coupled receptors (GPCRs) are one such integral membrane proteins involved in signal transduction and constitute major drug targets for a broad range of disease therapies including asthma, neurological disorders, immune dysfunction and cancer. Thus the demand for specific inhibitors and regulators of protein kinases and phosphatases is high and of utmost interest in the field of biomedical research. Although antibody mediated stabilization of GPCRs or other proteins is a formidable advance, its widespread utility remains limited by problems associated with:

  • Immunogenicity
  • Economic feasibility
  • Time consuming nature of immunization
  • Library construction

Aptamers have demonstrated great potential as valuable conformation sensors and pharmacologic agents for GPCRs due to their advantages such as:

  • Vast library diversity
  • Easily synthesized and modified for added stability
  • High selectivity and affinity because of their unique 3D conformations
  • Favorable pharmacokinetic and pharmacodynamics properties
  • Easy transportation and storage

Taking into consideration the importance of GPCR receptors and their importance in human health and diseases, following review provides therapeutic applications of aptamers in modulating and neutralizing GPCRs.

Aptamers as neutralizing agents

Autoimmunity and autoantibodies play a role in the pathogenesis of many diseases. One such example includes the presence of functional autoantibodies (GPCR-AABs, presently known as pathogenic drivers for diseases of the cardiovascular system) against G-protein bound receptors in serum from patients with Alzheimer’s and vascular dementia. Wallukat et al., 2016 demonstrated in vivo GPCR-ABB neutralizing potency by DNA aptamer called BC007 in beta1-AAB positive rats. Based on the binding and epitope-mapping studies, BC007 aptamer showed selectivity for the GPCR-AAB FAB fragment clearly outside the complementary determining regions (CDRs) which explains the surprising potency of BC007 for the neutralization of most several GPCR-ABBs.

Aptamer BC007’s effect on IgG prepared from the serum of beta-AAB positive DCM patients showed significant benefit with strong reduction in the beta1-AAB titer, which did not substantially return in the follow-up after twelve months. The successful neutralization of GPCR-AABs by BC007 aptamers suggested a possibility of being a potential therapeutic tool for dementia patients and is currently undergoing clinical trials.

Aptamers as allosteric modulators

Kahsai et al., 2016 identified aptamers that function as allosteric modulators by precise modulation of the activation and signaling cascade of GPCR. Characterizing such ligand-selective signaling conformations could serve as the basis for the design of GPCR ligands with:

  • Better efficacy
  • Improved safety profile
  • An enhanced therapeutic window

By involving next generation sequencing and a specific selection strategy, the researchers identified RNA aptamers that bound selectively to active and inactive receptor conformations of prototypical GPCR namely, β2-adrenoceptor (β2-AR). For example, one group of aptamers (A1, A2 and A13) showed high affinity for agonist active β2-AR conformation, whereas, another aptamer termed A16 showed specificity for an inverse-agonist inactive β2-AR conformation. This way the aptamers were able to stabilize different confirmations of β2-AR receptor. With this study, the researchers illustrated the great potential of aptamers to act as tailored allosteric modulators of GPCRs.

Overall aptamers could provide a strong tool for the expansion of new therapeutic factors in various infections and diseases. Looking at the bigger picture, aptamers have a tendency to act as therapeutic molecules for suppressing, neutralizing or inhibiting GPCR or other protein receptors related to COVID-19 such as ACE2, thereby stopping viral replication.

At Aptamer Group Limited (AGL), we have developed our selection process tailored to customer requirements such as introducing specific buffers, matrices, and most importantly counter-selection steps to ensure that the aptamers are selective to the target of interest. Our proprietary selection methodology rapidly identifies aptamers that can be used in a variety of diagnostic and therapeutic settings. This allows us to overcome many of the limitations associated with antibodies.

For more information regarding the applications of aptamers in therapeutics and how it can be best utilized in your research, please get in touch.


Kahsai AW, Wisler JW, Lee J, et al. Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor. Nat Chem Biol. 2016;12(9):709‐716.

Wallukat, G., Müller, J., Haberland, A., et al. (2016). Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G-protein coupled receptors: A vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies. Atherosclerosis, 244, 44–47.doi:10.1016/j.atherosclerosis.2015.11.001

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