Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.

The main proteases (M^pro), also termed 3‐chymotrypsin‐like proteases (3CL^pro), are a class of highly conserved cysteine hydrolases in β‐coronaviruses. Increasing evidence has demonstrated that 3CL^pros play an indispensable role in viral replication and have been recognized as key targets for preventing and treating coronavirus‐caused infectious diseases, including COVID‐19. This review is focused on the structural features and biological function of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease M^pro (also known as 3CL^pro), as well as recent advances in discovering and developing SARS‐CoV‐2 3CL^pro inhibitors. To better understand the characteristics of SARS‐CoV‐2 3CL^pro inhibitors, the inhibition activities, inhibitory mechanisms, and key structural features of various 3CL^pro inhibitors (including marketed drugs, peptidomimetic, and non‐peptidomimetic synthetic compounds, as well as natural compounds and their derivatives) are summarized comprehensively. Meanwhile, the challenges in this field are highlighted, while future directions for designing and developing efficacious 3CL^pro inhibitors as novel anti‐coronavirus therapies are also proposed. Collectively, all information and knowledge presented here are very helpful for understanding the structural features and inhibitory mechanisms of SARS‐CoV‐2 3CL^pro inhibitors, which offers new insights or inspiration to medicinal chemists for designing and developing more efficacious 3CL^pro inhibitors as novel anti‐coronavirus agents.