Anti-S SOMAmers as functional probes and potential therapeutic agents for Covid19
Lead supervisor: prof william james, sir william dunn school of pathology
Industrial partner: Somalogic, Boulder (USA), and UK
Aptamers are ligands composed of nucleic acid that are isolated by cycles of affinity selection and amplification from massive combinatorial libraries. In this project, we will build on our pioneering work, demonstrating the effectiveness of neutralizing aptamers to lentiviruses and herpesviruses, which confirmed our hypothesis that, owing to their relatively small size, aptamers could bind to sites on viral envelope glycoproteins that were sterically shielded from antibodies, and so remained evolutionarily conserved. SomaLogic have developed a novel chemistry in which aptamers with aromatic/hydrophobic 5-dU substitutions (SOMAmers) provide sub-nanomolar ligands of biological macromolecules, with applications in many areas of the biological sciences, including therapeutics, immunohistochemistry, fluorescent microscopy, cytopathology, and proteomics (SomaScan Array technology). Oxford has developed a unique strategic relationship with the company, SomaLogic, Boulder CO, who developed this approach, to take their development further through a UK-based subsidiary. SomaLogic have now isolated a large library of SOMAmer reagents that bind with sub-nanomolar affinity to different parts of the SARS-CoV-2 Spike glycoprotein. In this project, the student will study the neutralizing potential of these aptamers, and will go on to use structural information on the SOMAmer binding sties, obtained by our collaborators at STRUBI, to design and test bivalent or multivalent SOMAmers with the potential to bind with greater affinity, and to both the “closed” conformation of the spike, found in free virions, and the “open” form transiently available during the cellular infection process. The potential of such agents as potent anti-coronavirus agents is evident. The physicochemical stability and low cost of bulk synthesis of oligonucleotides such as SOMAmers offers a realistic route for commercial exploitation of these agents in low-cost and low-tech administration to respiratory and enteric epithelia for viruses of both veterinary and medical importance.