Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (Mpro, also named 3CLpro) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 Mpro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent Mpro inhibitor (27h) with an IC50 value of 10.9 nM. The crystal structure of Mpro in complex with 27h revealed that α-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC50 value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for Mpro against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 Mpro and deserves further in-depth studies.

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants.

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

Demulsification Performance and Mechanism of Tertiary Amine Polymer-Grafted Magnetic Nanoparticles in Surfactant-Free Oil-in-Water Emulsion.

Numerous cationic magnetic nanoparticles (MNPs) have previously been developed for demulsifying oil-in-water (O/W) emulsion, and results showed that the cationic MNPs could effectively flocculate and remove the negatively charged oil droplets via charge attraction; however, to the best of our knowledge, there are no research reports regarding the synergetic influence of both the positive charge density and interfacial activity of MNPs on the demulsification performance. In this study, three tertiary amine polymer-grafted MNPs, namely, poly(2-dimethylaminoethyl acrylate)-grafted MNPs (M-PDMAEA), poly(2-dimethylamino)ethyl methacrylate)-grafted MNPs (M-PDMAEMA), and poly(2-diethylaminoethyl methacrylate)-grafted MNPs (M-PDEAEMA), were synthesized and evaluated for their demulsification performance. Results demonstrated that a high positive charge density and superior interfacial activity of MNPs could cause partial oil droplet re-dispersion when excessive MNPs were introduced, leading to a lower magnetic separation efficiency and narrower demulsification window. Herein, a demulsification window is defined as a range of nanoparticle dosages in which the MNPs can effectively demulsify the O/W emulsion under certain conditions. For highly positively charged MNPs, their good interfacial activity could aggravate the formation of a narrower demulsification window. When tertiary amine polymer-grafted MNPs carried a lower positive charge density or weak interfacial activity, that is, M-PDMAEA at pH 4.0, M-PDMAEMA at pH 5.0-9.0, and M-PDEAEMA at pH 9.0-10.0, wide demulsification windows were observed. Additionally, a recycling experiment suggested that MNPs could maintain high demulsification efficiency up to at least five cycles, indicating their satisfactory recyclability. The three tertiary amine polymer-grafted MNPs can be potentially used for efficient demulsification from surfactant-free O/W emulsion in various pH ranges.

Non-classical ferroptosis inhibition by a small molecule targeting PHB2.

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.

Discovery of 2-vinyl-10H-phenothiazine derivatives as a class of ferroptosis inhibitors with minimal human Ether-a-go-go related gene (hERG) activity for the treatment of DOX-induced cardiomyopathy.

Ferroptosis was an iron-dependent, nonapoptotic form of regulated cell death. In our previous study, we discovered a potent ferroptosis inhibitor with phenothiazine scaffold (1), but subsequent investigation showed that this compound had potent hERG binding affinity. Herein, we report the discovery of a series of 2-vinyl-10H-phenothiazine derivatives as new class of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the identification of compound 7j, which exhibited significantly reduced hERG inhibition (IC50 > 30 µM) while maintaining high ferroptosis inhibitory activity (EC50 = 0.001 µM on the erastin-induced HT1080 cell ferroptosis model). Further studies confirmed 7j acted as a ROS scavenger and could relieve DOX-induced cardiomyopathy. 7j also displayed favorable pharmacokinetic properties and exhibited no obvious toxicity in vivo and vitro. Overall, this study provides a promising lead compound for drug discovery targeting ferroptosis.

Epigenetic regulation by polycomb group complexes: focus on roles of CBX proteins.

Polycomb group (PcG) complexes are epigenetic regulatory complexes that conduct transcriptional repression of target genes via modifying the chromatin. The two best characterized forms of PcG complexes, polycomb repressive complexes 1 and 2 (PRC1 and PRC2), are required for maintaining the stemness of embryonic stem cells and many types of adult stem cells. The spectra of target genes for PRCs are dynamically changing with cell differentiation, which is essential for proper decisions on cell fate during developmental processes. Chromobox (CBX) family proteins are canonical components in PRC1, responsible for targeting PRC1 to the chromatin. Recent studies highlight the function specifications among CBX family members in undifferentiated and differentiated stem cells, which reveal the interplay between compositional diversity and functional specificity of PRC1. In this review, we summarize the current knowledge about targeting and functional mechanisms of PRCs, emphasizing the recent breakthroughs related to CBX proteins under a number of physiological and pathological conditions.