Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I.

The monkeypox outbreak has become a global public health emergency. The lack of valid and safe medicine is a crucial obstacle hindering the extermination of orthopoxvirus infections. The identification of potential inhibitors from natural products, including Traditional Chinese Medicine (TCM), by molecular modeling could expand the arsenal of antiviral chemotherapeutic agents. Monkeypox DNA topoisomerase I (TOP1) is a highly conserved viral DNA repair enzyme with a small size and low homology to human proteins. The protein model of viral DNA TOP1 was obtained by homology modeling. The reliability of the TOP1 model was validated by analyzing its Ramachandran plot and by determining the compatibility of the 3D model with its sequence using the Verify 3D and PROCHECK services. In order to identify potential inhibitors of TOP1, an integrated library of 4103 natural products was screened via Glide docking. Surface Plasmon Resonance (SPR) was further implemented to assay the complex binding affinity. Molecular dynamics simulations (100 ns) were combined with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations to reveal the binding mechanisms of the complex. As a result, three natural compounds were highlighted as potential inhibitors via docking-based virtual screening. Rosmarinic acid, myricitrin, quercitrin, and ofloxacin can bind TOP1 with KD values of 2.16 µM, 3.54 µM, 4.77 µM, and 5.46 µM, respectively, indicating a good inhibitory effect against MPXV. The MM/PBSA calculations revealed that rosmarinic acid had the lowest binding free energy at -16.18 kcal/mol. Myricitrin had a binding free energy of -13.87 kcal/mol, quercitrin had a binding free energy of -9.40 kcal/mol, and ofloxacin had a binding free energy of -9.64 kcal/mol. The outputs (RMSD/RMSF/Rg/SASA) also indicated that the systems were well-behaved towards the complex. The selected compounds formed several key hydrogen bonds with TOP1 residues (TYR274, LYS167, GLY132, LYS133, etc.) via the binding mode analysis. TYR274 was predicted to be a pivotal residue for compound interactions in the binding pocket of TOP1. The results of the enrichment analyses illustrated the potential pharmacological networks of rosmarinic acid. The molecular modeling approach may be acceptable for the identification and design of novel poxvirus inhibitors; however, further studies are warranted to evaluate their therapeutic potential.

Deguelin inhibits HCV replication through suppressing cellular autophagy via down regulation of Beclin1 expression in human hepatoma cells.

AIMS: Deguelin, a natural compound derived from Mundulea sericea (Leguminosae) and some other plants exhibits an activity to inhibit autophagy, a cellular machinery required for hepatitis C virus (HCV) replication. This study aimed to illuminate the impact of deguelin on HCV replication and mechanism(s) involved. METHODS: HCV JFH-1-Huh7 infectious system was used for the investigation. Real time RT-PCR, Western blot, fluorescent microscopy assay were used to measure the expression levels of viral or cellular factors. Overexpression and silencing expression techniques were used to determine the role of key cellular factors. RESULTS: Deguelin treatment of Huh7 cells significantly inhibited HCV JFH-1 replication in a dose- and time-dependent manner. Deguelin treatment suppressed autophagy in Huh7 cells, evidenced by the decrease of LC3B-II levels, the conversion of LC3B-I to LC3B-II, and the formation of GFP-LC3 puncta as well as the increase of p62 level in deguelin-treated cells compared with control cells. HCV infection could induce autophagy which was also suppressed by deguelin treatment. Mechanism research reveals that deguelin inhibited expression of Beclin1, which is a key cellular factor for the initiation of the autophagosome formation in autophagy. Overexpression or silencing expression of Beclin1 in deguelin-treated Huh7 cells could weaken or enhance the inhibitory effect on autophagy by deguelin, respectively, and thus partially recover or further inhibit HCV replication correspondingly. CONCLUSIONS: Deguelin may serve as a novel anti-HCV compound via its inhibitory effect on autophagy, which warrants further investigation as a potential therapeutic agent for HCV infection.

A novel xanthone dimer derivative with antibacterial activity isolated from the bark of Garcinia mangostana.

A novel xanthone dimer derivative, garmoxanthone (1), together with 10 known compounds (2-11), were isolated from bark of Garcinia mangostana. Their structures were established through spectroscopic methods. Garmoxanthone exhibited strong inhibitory activities against MRSA ATCC 43300 and MRSA CGMCC 1.12409 (with MIC values of both 3.9 µg/mL) and moderate activities against tested strains of Vibrio (with MIC values ranging from 15.6 to 31.2 µg/mL). Garmoxanthone is a unique xanthone dimer with linkage of a fused 5/6 ring system and its absolute configuration was elucidated on the basis of experimental and calculated electronic circular dichroism. Garmoxanthone exhibited strong antibacterial activity which partially validated the ethnobotanical use of G. mangostana in the treatment of infections.

Flos lonicerae extracts and chlorogenic acid protect human umbilical vein endothelial cells from the toxic damage of perfluorooctane sulphonate.

Chlorogenic acid (CGA), one of the most common phenolic acids, is found in many food and traditional Chinese herbs. Various bioactivities of CGA are studied. However, little is known about these properties of Flos Lonicerae extracts, and the difference in the effect between Flos Lonicerae extracts and CGA has not been reported. CGA was identified in Flos Lonicerae extracts by HPLC and determined qualitatively by quadrupole ion trap mass spectrometry. In this study, we evaluated the effect of Flos Lonicerae extracts and CGA on inflammatory-related gene expression, adhesion molecule expression and reactive oxygen species (ROS) production in perfluorooctane sulphonate (PFOS)-treated human umbilical vein endothelial cells (HUVECs). The suppression of transcription of IL-1ß, IL-6, COX-2, and P-Selectin genes with Flos Lonicerae extracts was greater than that of CGA in PFOS-treated HUVECs, while the degree of suppression on PFOS-induced expression of NOS3 and ICAM-1 was greater for CGA. Furthermore, the suppressive effect of Flos Lonicerae extracts on adhesion of monocytes onto PFOS-induced HUVECs was greater than that of CGA. In addition, Flos Lonicerae extracts and CGA were highly effective in reducing ROS although their effects were almost comparable. So, Flos Lonicerae extracts exhibited antioxidant activity and CGA was a major contributor to this activity. These results suggest that Flos Lonicerae extracts could be useful to prevent PFOS-mediated inflammatory diseases.