Carmofur

In severe COVID-19 cases, an exacerbated inflammatory response triggers a cytokine storm that can worsen the prognosis. Compounds with both antiviral and anti-inflammatory activities show promise as candidates for COVID-19 therapy, as they potentially act against the SARS-CoV-2 infection regardless of the disease stage. One of the most attractive drug targets among coronaviruses is the main protease (MPro). This enzyme is crucial for cleaving polyproteins into non-structural proteins required for viral replication. The aim of this review was to identify SARS-CoV-2 MPro inhibitors with both antiviral and anti-inflammatory properties. The interactions of the compounds within the SARS-CoV-2 MPro binding site were analyzed through molecular docking when data from crystallographic structures were unavailable. 18 compounds were selected and classified into five different superclasses. Five of them exhibit high potency against MPro: GC-376, baicalein, naringenin, heparin, and carmofur, with IC₅₀ values below 0.2 μM. The MPro inhibitors selected have the potential to alleviate lung edema and decrease cytokine release. These molecules mainly target three critical inflammatory pathways: NF-κB, JAK/STAT, and MAPK, all previously associated with COVID-19 pathogenesis. The structures of the compounds occupy the S1/S2 substrate binding subsite of the MPro. They interact with residues from the catalytic dyad (His41 and Cys145) and/or with the oxyanion hole (Gly143, Ser144, and Cys145), which are pivotal for substrate recognition. The MPro SARS-CoV-2 inhibitors with potential anti-inflammatory activities present here could be optimized for maximum efficacy and safety and be explored as potential treatment of both mild and severe COVID-19.

Differentiation of induced pluripotent stem cells (iPSCs) is an extremely complex process that has proven difficult to study. In this research, we utilized nanotopography to elucidate details regarding iPSC differentiation by developing a nanodot platform consisting of nanodot arrays of increasing diameter. Subjecting iPSCs cultured on the nanodot platform to a cardiomyocyte (CM) differentiation protocol revealed several significant gene expression profiles that were associated with poor differentiation. The observed expression trends were used to select existing small-molecule drugs capable of modulating differentiation efficiency. BRD K98 was repurposed to inhibit CM differentiation, while iPSCs treated with NSC-663284, carmofur, and KPT-330 all exhibited significant increases in not only CM marker expression but also spontaneous beating, suggesting improved CM differentiation. In addition, quantitative polymerase chain reaction was performed to determine the gene regulation responsible for modulating differentiation efficiency. Multiple genes involved in extracellular matrix remodeling were correlated with a CM differentiation efficiency, while genes involved in the cell cycle exhibited contrasting expression trends that warrant further studies. The results suggest that expression profiles determined via short time-series expression miner analysis of nanodot-cultured iPSC differentiation can not only reveal drugs capable of enhancing differentiation efficiency but also highlight crucial sets of genes related to processes such as extracellular matrix remodeling and the cell cycle that can be targeted for further investigation. Our findings confirm that the nanodot platform can be used to reveal complex mechanisms behind iPSC differentiation and could be an indispensable tool for optimizing iPSC technology for clinical applications.