Advances in the design of ligands interacting with 3CL protease of novel coronaviruses causing infectious respiratory syndrome
Two newly isolated coronaviruses (CoVs) cause the severe pneumonia-like respiratory illnesses, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Neither therapeutic agents nor vaccines have been developed thus far, and even future pandemics of related infectious diseases are expected through zoonotic virus infections. Since the 3C like (3CL) protease of SARS/MERS CoV, which has structural similarities with the 3C protease of rhinovirus causing common cold in humans, is essential to the proliferation of SARS/MERS CoV, inhibition of the 3CL protease (3CLpro) is thought to be an ideal target for the development of therapeutic agents against SARS and MERS. This article describes the recent achievements in the development of inhibitors of the SARS/MERS 3CLpro mainly based on two different approaches: one by combining a peptide-like structure with a reactive functional group, a so-called “warhead,” and a second one by combining virtual screening and high-throughput screening of a real compound library. A recent approach based on the structure-based rational design of a novel inhibitor scaffold for 3CLpro is also included.