The Wuhan coronavirus, also known as COVID-19, SARS-CoV-2, or 2019-nCoV, is a close relative to the severe acute respiratory syndrome (SARS) virus that caused an outbreak in 2003 (SARS-CoV-1), as well as the Middle-East respiratory disease virus (MERS-CoV) that emerged in 2012. All of these viruses cause flu-like symptoms and, frequently, pneumonia. However, no effective treatments have been developed, in part because the relatively small number of cases have not warranted large expenditures by pharmaceutical companies. Hong Liu, Rolf Hilgenfeld and colleagues envisioned a possible solution in the form of broad-spectrum antiviral drugs that target all coronaviruses, as well as enteroviruses — some of which cause conditions like the common cold; hand, foot and mouth disease; and the “summer flu.” All of these viruses share a similar protein-cutting enzyme, called the “main protease” in coronaviruses and the “3C protease” in enteroviruses, that is essential for viral replication. The researchers examined X-ray crystal structures of the proteases and then made a series of α-ketoamide compounds that were predicted to fit snugly in the enzymes’ active sites, interfering with their function. By testing the molecules in the test tube and in human cells in petri dishes, they identified one versatile inhibitor that blocked multiple coronaviruses and enteroviruses, including SARS-CoV-1. Another molecule showed very strong activity against MERS-CoV, with moderate activity against the other viruses. Because the main proteases of COVID-19, MERS-CoV and SARS-CoV-1 are very similar, the inhibitors will most likely show good antiviral activity against the Wuhan coronavirus, the researchers say. Their next step will be to test the inhibitors in small-animal models of disease. Reference: “α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment” by Linlin Zhang, Daizong Lin, Yuri Kusov, Yong Nian, Qingjun Ma, Jiang Wang, Albrecht von Brunn, Pieter Leyssen, Kristina Lanko, Johan Neyts, Adriaan de WildeEric J. Snijder, Hong Liu and Rolf Hilgenfeld, 11 February 2020, Journal of Medicinal Chemistry.DOI: 10.1021/acs.jmedchem.9b01828 The authors acknowledge funding from the European Commission SILVER project, the German Center for Infection Research and the National Natural Science Foundation of China.
