RESUMO
The main protease (M pro) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M pro. Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M pro and seven M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M pros. In addition, the crystal structures of SARS-CoV-2 M pro, SARS-CoV M pro, MERS-CoV M pro, and seven SARS-CoV-2 M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M pros. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M pro inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.
RESUMO
Sinomenine, an isoquinoline alkaloid extracted from the roots and stems of Sinomenium acutum, has been extensively studied for its derivatives as bioactive agents. This review concentrates on the research advancements in the biological activities and action mechanisms of sinomenine-related compounds until November 2023. The findings indicate a broad spectrum of pharmacological effects, including antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties. These compounds are notably effective against breast, lung, liver, and prostate cancers, exhibiting IC50 values of approximately 121.4 nM against PC-3 and DU-145 cells, primarily through the PI3K/Akt/mTOR, NF-κB, MAPK, and JAK/STAT signaling pathways. Additionally, they manifest anti-inflammatory and analgesic effects predominantly via the NF-κB, MAPK, and Nrf2 signaling pathways. Utilized in treating rheumatic arthritis, these alkaloids also play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection through the NF-κB, Nrf2, MAPK, and PI3K/Akt/mTOR signaling pathways. This review concludes with perspectives and insights on this topic, highlighting the potential of sinomenine-related compounds in clinical applications and the development of medications derived from natural products.
Assuntos
Alcaloides , Morfinanos , Masculino , Humanos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt , Fator 2 Relacionado a NF-E2 , Fosfatidilinositol 3-Quinases , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Morfinanos/farmacologia , Serina-Treonina Quinases TOR , Alcaloides/farmacologiaRESUMO
In this study Paraccocus versutus XT0.6 was employed to address the mechanism of microbial dissolution and oxidation of stibnite. Results showed that with the growth of XT0.6, pH increased to 9.0 in both microbe-mineral contact (MM) and microbe-mineral non-contact groups (M[M]). Dissolved Sb(III) was released from stibnite, which was subsequently quickly oxidized to Sb(V) completely in MM and partially in M[M] groups. On the contrast, the final pH decreased to 6.5 and 4.9, respectviely, in system amended with extracellular secretion (EM) of XT0.6 and abiotic groups. Dissolution of stibnite and oxidation of Sb(III) were also observed in EM group, suggesting a potential contribution of extracellular enzyme in Sb(III) oxidation. The dissolution and oxidation rates were the highest in MM group, followed by those in M[M], EM and abiotic groups. To be noted, Sb(V) concentration decreased in MM group on the fifth day, which might indicate the formation of Sb(V)-bearing secondary mineral. Genome of XT0.6 consisted of two chromosomes and one plasmid, and most genes responsible for antimony oxidation and antimony resistance were located on the chromosomes. Proteomics analysis of the extracellular secretions indicated the up-regulated proteins were mainly related to electron-transfer, suggesting their potential role in Sb(III) oxidation.