Immel Jacob R, Chilamari Maheshwerreddy, Bloom Steven
Department of Medicinal Chemistry, The University of Kansas Integrated Science Building Lawrence KS 66045 USA
Chem Sci. 2021 Jun 30;12(29):10083-10091. doi: 10.1039/d1sc02562g. eCollection 2021 Jul 28.
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 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.
大多数肽类药物都含有非蛋白质ogenic氨基酸（NPAAs），这些氨基酸是通过使用固相肽合成（SPPS）进行广泛的构效关系（SAR）研究而产生的。NPAAs合成费力且生产成本高昂，其偶联效率也可能很低，以至于传统的SPPS只能对一小部分进行取样。为了能够普遍获得含NPAA的肽，我们开发了第一代平台，该平台将当代黄素光催化与平行合成相结合，以同时制备、纯化、定量甚至测试多达96种单-NPAA肽变体——肽中硼酸和脱氢丙氨酸残基的独特组合。我们展示了这个新创建的平台的强大功能，它能够将不同化学类型的NPAAs——脂肪族、芳香族、杂芳香族——直接引入肽中，包括15个全新的残基，并通过非经典肽SAR将一种简单的蛋白质ogenic肽演变成一种非天然的凝血酶抑制剂。
