Pomplun, Sebastian

Massachusetts Institute of Technology (USA)


Combinatorial discovery of synthetic biohybrid ligands for RNA-hairpins and for the SARS-CoV-2- spike protein


The de novo discovery of ligands for challenging and novel drug targets often requires the cumbersome screening of individual compounds from large libraries. Here we present a fully chemistry based affinity selection – mass spectrometry (AS-MS) platform: within days synthetic polyamide compound libraries with > 100 million members can be produced, screened against targets of interest and originate hits with nanomolar affinity for their targets. We use AS-MS for the rapid discovery of synthetic high-affinity peptide binders for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The peptides display excellent selectivity for RBD over human serum proteins and can detect picomolar RBD concentrations in a biological matrix. We further expanded the AS-MS platform for the discovery of compounds targeting oncogenic pre-miRNA hairpins.

In nature nucleic acids are often controlled by large supramolecular protein/oligonucleotide complexes as in the case of ribosomal protein synthesis. Rather than forming large complexes to coordinate the role of different biopolymers, we dovetail protein amino acids and nucleobases into a single low molecular weight precision polyamide polymer. We established efficient chemical synthesis and de novo sequencing procedures and prepared combinatorial libraries with up to 100 million biohybrid molecules. This biohybrid material has a higher bulk affinity to oligonucleotides than peptides composed exclusively of canonical amino acids. Using affinity selection mass spectrometry, we discovered variants with a high-affinity for pre-microRNA hairpins. Our platform points toward the development of high throughput discovery of sequence defined polymers with designer properties, such as oligonucleotide binding.

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