Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and persistently threatens to humanity. With tireless efforts from scientists around the world, understanding of the biology of coronavirus has been greatly enhanced over the past 2 years. Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19. In this review, we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed. We present the examples of structure-based design of Pfizer's novel anti-SARS-CoV-2 drug PF-07321332 (Paxlovid), Merck's nucleotide inhibitor molnupiravir (Lagevrio), and VV116, an oral drug candidate for COVID-19. These examples highlight the importance of structure in drug discovery to combat COVID-19. We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies.

Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase.

Kidney-type glutaminase (KGA), catalyzing the hydrolysis of glutamine to glutamate for energy supply, is over-expressed in many cancers and has been regarded as a new therapeutic target for cancers. Physapubescin I was isolated from the fruits of the edible herb Physalis pubescens L., commonly named as "husk tomato or hairy groundcherry", and was predicted to be a potential KGA inhibitor through structure-based virtual ligand screening. Enzyme inhibition assays, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) experiments have demonstrated the high efficiency and specificity of physapubescin I targeting KGA. EdU proliferation, Hoechst 33258 staining and cytotoxicity assays indicated that physapubescin I could inhibit cancer cell proliferation and promote apoptosis more effectively than the known KGA inhibitor, BPTES. Knockdown of KGA by siRNA reduced the inhibition of physapubescin I to SW1990 cells. Meanwhile, physapubescin I impaired glutamine metabolism in SW1990 cells with increasing intracellular level of glutamine, and correspondingly decreasing glutamate and its downstream metabolites, which may account for its inhibition of cancer cell proliferation and proapoptosis. Physapubescin I also showed significant tumor growth inhibition and low toxicity in a SW1990 xenograft mouse model. Collectively, physapubescin I may serve as a potential drug candidate or lead compound for cancer therapy by targeting KGA.

Chemical constituents of Pholidota cantonensis.

Two 9,10-dihydrophenanthrenes trivially named phocantol and phocantone, two diterpenoid glycosidesnamed phocantoside A and phocantoside B were isolated from the ethanol extract of the air-dried whole plant of Pholidota cantonensis Rolfe, together with seventeen known compounds. The structures of the four compounds were identified as 1-hydroxy-2,7-dimethoxy-9,10-dihydrophenanthro-[4,5-bcd]furan, 5-hydroxy-2,7-dimethoxy-9,10-dihydro-1,4-phenanthrenedione, (8R,13E)-ent-labd-13-ene-3α,8,15-triol 15-O-ß-D-gluco-pyranoside and (5S,8R,9S,10R)-cis-cleroda-3,13(E)-diene-15,18-diol 15-O-ß-D-glucopyranosyl-18-O-ß-D-glucopyranoside by chemical and spectroscopic methods, including 1D and 2D NMR. Twenty compounds were evaluated for their cytotoxic activities against mouse leukemia p388D1 cancer cells, and compound phocantone, phocantoside A, tanshinone IIA and syringate exhibited cytotoxic activity against the mouse leukemia p388D1 cancer cells with IC50 values ranging from 13.37 to 27.5 µM.

Physapubescin, a natural withanolide as a kidney-type glutaminase (KGA) inhibitor.

Kidney-type glutaminase (KGA) is over expressed in many kinds of cancers that converts glutamine to glutamate for supplying energy, and has become an object for targeted cancer therapy. The structure-based virtual ligand screening identified physapubescin, a withanolide purified from Physalis pubescens L., as a possible inhibitor of KGA with low binding energy. Enzyme inhibition experiments and cell-based assays further confirmed its inhibitory effects on KGA activity, suggesting potential applications of physapubescin and its derivatives as KGA inhibitors.

[Effect of Jiangang Yishen Recipe on high insulin induced cell proliferation of human glomerular mesangial cells and the expression of insulin receptor substrate 1 and phosphatidylinositol-3-kinase].

OBJECTIVE: To investigate the effect of Jiangtang Yishen Recipe (JTYSR) on high insulin induced cell proliferation of human glomerular mesangial cells (HMCs) and the expression of insulin receptor substrate 1 (IRS-1) and phosphatidylinositol-3-kinase (PI-3K). METHODS: HMCs were divided into 4 groups, i.e., the negative control group, the high insulin model group, the JTYSR group, and the LY294002 group. The concentration of insulin, JTYSR, and LY294002 was respectively confirmed by pre-experiment. Different culture solution was respectively added for different groups. RPMI1640 culture solution was added for HMCs in the negative control group, while HMCs in the rest 3 groups were cultured by 100 nmol/L insulin for 24 h. Meanwhile, HMCs from the JTYSR group and the LY294002 group were exposed to 125 mg/L JTYSR and 80 micromol/L LY294002 respectively for further 48 h. The proliferation of HMCs was detected by MTT and flow cytometry. The protein expression of IRS-1 and PI-3K in HMC was detected by immunohistochemical assay and Western blot. Results The proliferation of HMCs induced by high insulin could be significantly lowered, and the protein expression of IRS-1 and PI-3K could be down-regulated in the JTYSR group and the LY294002 group (P <0.01). Compared with the LY294002 group, the protein expression of IRS-1 and PI-3K could be slightly down-regulated in the JTYSR group (P <0.05). CONCLUSION: JTYSR could lower high insulin induced proliferation of HMCs, and its mechanism might be related to insulin signaling pathway.

Effects of QWBZP on T-cell subsets and their cytokines in intestinal mucosa of HRV infection suckling mice.

AIM OF THIS STUDY: Qiwei Baizhu Powder (QWBZP) is a traditional herbal prescription that has been used traditionally for the treatment of infantile diarrhea, including the infantile diarrhea caused by Human Rotavirus (HRV). In this study, we investigated the pharmacological activity of QWBZP extract. MATERIALS AND METHODS: NIH suckling mice with HRV induced diarrhea were used. Density of CD3(+), CD4(+) and CD8(+) T cells, mRNA expression of IL-2, IFN-gamma, IL-4 and IL-10 in intestinal mucosa epithelial cells were assayed. RESULTS: QWBZP extract promoted the expressions of mRNA of IL-2, IL-4, IL-10 and IFN-gamma in intestinal mucosa epithelial cells. Also, we found that the density of CD8(+) cells in intestinal mucosa epithelial cells was significantly lower in QWBZP group than in Model group, while the density of CD8(+) cells was significantly higher in QWBZP group than in Model group. CONCLUSION: These data suggest that QWBZP extract may exhibit antiviral effects through modulating the densities of T-cell subsets and the expressions of their cytokines in small intestinal mucosa epithelial cells.

[Experimental research of songzhi pills on inducement of interferon in mice and rats].

OBJECTIVE: To develop a new drug of treating the hepatitis C virus by studing the mechanisms of songzhi pills. METHOD: The four-wee old mice and two-month old rats were chosen to induce interferon. RESULT: The contents of interferon among the groups treated with songzhi pills were significantly higher than those of the normal group and the model group (P < 0.01), CONCLUSIONS: Songzhi pills may have the function of inducing interferon.