Button-Push\nOn-Demand Synthesis for Rapid Optimization\nof Antiviral Peptidomimetics

The\noptimization of hit compounds into drug candidates is a pivotal\nphase in drug discovery but often hampered by cumbersome manual synthesis\nof derivatives. While automated organic molecule synthesis has enhanced\nefficiency, safety, and cost-effectiveness, achieving fully automated\nmultistep synthesis remains a formidable challenge due to issues such\nas solvent and reagent incompatibilities and the accumulation of side-products.\nWe herein demonstrate an automated solid-phase flow platform for synthesizing\nα-keto-amides and nitrile peptidomimetics, guided by docking\nsimulations, to identify potent broad-spectrum antiviral leads. A\ncompact parallel synthesizer was built in-house, capable of producing\n5 distinct molecules per cycle; 525 reactions could be finished within\nthree months to generate 42 derivatives for a structure–activity\nrelationship (SAR) investigation. Among these, ten derivatives exhibited\npromising target inhibitory activity (IC<sub>50</sub> < 100 nM)\nincluding two with antiviral activity (EC<sub>50</sub> < 250 nM).\nThe platform, coupled with digital chemical recipe files, offers rapid\naccess to a wide range of peptidomimetics, serving as a valuable reservoir\nfor broad-spectrum antiviral candidates. This automated solid-phase\nflow synthesis approach expedites the generation of previously difficult\ncomplex molecular scaffolds. By integration of SPS-flow synthesis\nwith medicinal chemistry campaign, >10-fold target inhibitory activity\nwas achieved from a small set of derivatives, which indicates the\npotential to shift the paradigm of drug discovery.