New drug design strategy targets COVID-19 virus's main protease
Researchers have developed a faster way to design antiviral drugs by starting with tiny molecular fragments and building them up to hit a critical COVID-19 target. The approach produced a compound that binds effectively to the virus's main protease, potentially accelerating the discovery of next-generation treatments for coronavirus variants.
Originaltitel: Targeting the main protease (M<sup>pro</sup>, nsp5) by growth of fragment scaffolds exploiting structure-based methodologies
<p>The main protease M<sup>pro</sup>, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with M<sup>pro</sup>. These investigations resulted in the four-armed compound 35b that binds directly to M<sup>pro</sup>. 35b could be cocrystallized with M<sup>pro</sup> revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.</p>