Combining flavin photocatalysis with parallel synthesis: a general platform to optimize peptides with non-proteinogenic amino acids

• Published in: Chemical science (Cambridge) Vol. 12; no. 29; pp. 183 - 191
• Main Authors: Immel, Jacob R, Chilamari, Maheshwerreddy, Bloom, Steven
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 28.07.2021; Royal Society of Chemistry; The Royal Society of Chemistry
• Subjects: Amino acids; Chemistry; Chemistry, Multidisciplinary; Peptides; Photocatalysis; Physical Sciences; Residues; Science & Technology; Solid phases; Synthesis; Thrombin; BORONIC ACIDS; CENTERED RADICALS; COMPLEX; CHIRAL DEHYDROALANINES; NMR-SPECTROSCOPY; DIASTEREOSELECTIVE RADICAL-ADDITION; RESIDUES; DERIVATIVES; MICHAEL ADDITION; CONJUGATE ADDITION
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d1sc02562g

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. We report a non-classical approach to interrogate peptides with non-proteinogenic amino acids via flavin photocatalysis. We establish a new platform to make, purify, quantify, and biochemically test up to 96 peptide variants in batch.