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Combining flavin photocatalysis with parallel synthesis: a general platform to optimize peptides with non-proteinogenic amino acids
Immel, Jacob R. Chilamari, Maheshwerreddy Bloom, Steven
Immel, Jacob R.
Chilamari, Maheshwerreddy
Bloom, Steven
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Abstract
Most peptide drugs contain non-proteinogenic amino acids (NPAAs), born out through extensive structure–activity relationship (SAR) studies using solid-phase peptide synthesis (SPPS). Synthetically laborious and expensive to manufacture, NPAAs also can have poor coupling efficiencies allowing only a small fraction to be sampled by conventional SPPS. To gain general access to NPAA-containing peptides, we developed a first-generation platform that merges contemporary flavin photocatalysis with parallel synthesis to simultaneously make, purify, quantify, and even test up to 96 single-NPAA peptide variants via the unique combination of boronic acids and a dehydroalanine residue in a peptide. We showcase the power of our newly minted platform to introduce NPAAs of diverse chemotypes-aliphatic, aromatic, heteroaromatic-directly into peptides, including 15 entirely new residues, and to evolve a simple proteinogenic peptide into an unnatural inhibitor of thrombin by non-classical peptide SAR.
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2021-06-30
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Royal Society of Chemistry
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Immel, J. R., Chilamari, M., & Bloom, S. (2021). Combining flavin photocatalysis with parallel synthesis: a general platform to optimize peptides with non-proteinogenic amino acids. Chemical science, 12(29), 10083–10091. https://doi.org/10.1039/d1sc02562g