α-Ketoamides Keep Different Viruses from Multiplying

Antiviral drugs that target a variety of viruses, i.e., broad-spectrum antivirals, could be particularly useful to treat rare or new virus strains, such as the one currently causing the outbreak of COVID-19. This approach could be more commercially viable than developing a drug for every single disease caused by viruses and, thus, improve treatment options. To achieve broad activity, the drugs need a target that several viruses share. The very common enteroviruses, for example, depend on viral proteases to multiply. These proteases have similar active sites to the equivalent proteases in rarer coronaviruses, such as the SARS and MERS viruses, even though the viruses are very different overall.

Hong Liu, Shanghai Institute of Materia Medica, China, Rolf Hilgenfeld, Shanghai Institute of Materia Medica and University of Lübeck, Germany, and colleagues have developed α-ketoamides that could inhibit these proteases in coronaviruses and enteroviruses and, thus, prevent the replication of the viruses. The team used structure-based design, i.e., they analyzed crystal structures of the target proteases and of protease–inhibitor complexes. These structures were used to guide the optimization of the substituents at the α-ketoamides.

The researchers found that the best inhibitors have a γ-lactam derivative of glutamine and a cyclopentylmethyl or cyclohexylmethyl group next to the α-ketoamide unit. These inhibitors showed good activity against both enteroviruses and coronaviruses in cell cultures. The compounds showed only weak cytotoxicity. According to the team, due to the high similarity between the main proteases of the SARS virus and the new coronavirus that causes COVID-19, the developed inhibitors could also show antiviral activity against the new coronavirus.

• α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment,
  Linlin Zhang, Daizong Lin, Yuri Kusov, Yong Nian, Qingjun Ma, Jiang Wang, Albrecht von Brunn, Pieter Leyssen, Kristina Lanko, Johan Neyts, Adriaan de Wilde, Eric J. Snijder, Hong Liu, Rolf Hilgenfeld,
  J. Med. Chem. 2020.
  https://doi.org/10.1021/acs.jmedchem.9b01828

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