Abstract Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL pro ) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor ( R )‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide ( 2 b ), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL pro . Moreover, we report the discovery of isoindolines as a new class of potent PL pro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL pro are valuable starting points for the development of new pan‐coronaviral inhibitors. Valuable starting points : Within this study, the effectivity of naphthalene‐based inhibitors, formerly developed against the papain‐like protease (PL pro ) of the severe acute respiratory syndrome (SARS)‐causing coronavirus (CoV), against the homologous PL pro of SARS‐CoV‐2 is shown. Furthermore, isoindoline is presented as an innovative scaffold for this inhibitor type. In particular, high antiviral activity combined with low cytotoxicity are highlights of these inhibitors.
【저자키워드】 drug design, protease inhibitors, Antiviral agents, Computational chemistry, Structure-activity relationships, 【초록키워드】 coronavirus, Infection, cytotoxicity, protease, inhibition, antiviral activity, inhibitors, SARS‐CoV‐2, Replication, Cell culture, CoV, Pathogens, inhibitor, SAR, homologous, similarity, starting point, acute respiratory syndrome, cysteine protease, treat, highlight, shown, inhibit, binding mode, target proteases, 【제목키워드】 SARS‐CoV‐2, relationship, Benzamide, Isoindoline,