Chalcone-amide, a privileged backbone for the design and development of selective SARS-CoV/SARS-CoV-2 papain-like protease inhibitors

The newly emerged coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the COVID-19 pandemic, is the closest relative of SARS-CoV with high genetic similarity. The papain-like protease (PLpro) is an important SARS-CoV/SARS-CoV-2 nonstructural protein that plays a critical role in some infection processes such as the generation of the functional replication complex, maturation of crude polyproteins, and regulation of the host antiviral immune responses. Therefore, the research to discover SARS-CoV-2 PLpro inhibitors could be a sensible strategy to obtain therapeutic agents for the treatment of COVID-19. Aiming to find SARS-CoV/SARS-CoV-2 PLpro inhibitors, various high throughput screenings (HTS) have been performed over the past two decades. Interestingly, the result of these efforts is the identification of hit/lead compounds whose structures have one important feature in common, namely having a chalcone-amide (N-benzylbenzamide) backbone. Structure-activity relationship (SAR) studies have shown that placing an (R)-configurated methyl group on the middle carbon adjacent to the amide group creates a unique backbone called (R)-methyl chalcone-amide, which dramatically increases PLpro inhibitory potency. Although this scaffold has not yet been introduced by medicinal chemists as a specific skeleton for the design of PLpro inhibitors, structural considerations show that the most reported PLpro inhibitors have this skeleton. This review suggests the (R)-methyl chalcone-amide scaffold as a key backbone for the design and development of selective SARS-CoV-2 PLpro inhibitors. Understanding the SAR and binding mode of these inhibitors in the active site of SARS-CoV-2 PLpro can aid the future development of anti-COVID-19 agents.