Sands, D. | bioRxiv Science

bioRxiv2023

Dual inhibition of coronavirus Mpro and PLpro enzymes by phenothiazines and their antiviral activity

Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (Mpro) and papain-like protease (PLpro), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 Mpro and PLpro protease activity in vitro was identified. In silico docking studies also predicted binding of the phenothiazine to the active sites of Mpro and PLpro from distantly related alphacoronavirus, HCoV-229E (229E) and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cell culture infection models. It was further demonstrated that the compound inhibited 229E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/557219v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@fa2c92org.highwire.dtl.DTLVardef@844484org.highwire.dtl.DTLVardef@1ae5d5aorg.highwire.dtl.DTLVardef@730133_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICoronavirus cysteine proteases Mpro and PLpro are targets for novel antiviral agents C_LIO_LIPhenothiazine ureas inhibit SARS-CoV-2 Mpro and PLpro protease activity C_LIO_LISome phenothiazine ureas inhibit replication of diverse coronaviruses with minimal cytotoxicity C_LIO_LIPhenothiazine ureas inhibit early stages of coronavirus replication consistent with failure of viral polyprotein cleavage C_LI

microbiology↗

bioRxiv2021

Rapid screening methods of potato cultivars for low glycemic traits

Potatoes are a dietary staple consumed by a significant portion of the world, providing valuable carbohydrates and vitamins with minimal fat. Most commercially produced potatoes have a high content of highly branched amylopectin starch, which generally results in a high glycemic index (GI). Consumption of foods with high levels of amylopectin elicit a rapid spike in blood glucose levels, which is undesirable for individuals who are pre-diabetic, diabetic, or obese. Some cultivars of potatoes with lower amylopectin levels have previously been identified and are commercially available in niche markets in some countries but are relatively unavailable in the United States and Latin America. Among Native communities in North America and in the high Andes countries of South America, some foods that include certain potato cultivars, may have been used to help people mitigate what is now defined as the effects of blood sugar and obesity. These cultivars are not widely available on a global market. This study utilizes three independent analyses of potato starch: microscopic examination of granule structure, water absorption, and spectrophotometry of iodine complexes to identify potato cultivars with low amylopectin that are thought to have low GI potential. Differences among cultivars tested were detected by all three types of analyses. Of the 60 potato cultivars evaluated the most promising are Huckleberry Gold, Muru, Multa, Green Mountain, and an October Blue x Colorado Rose cross. Further work is necessary to document the ability of these low amylopectin cultivars to reduce blood glucose spike levels in human subjects.

plant biology↗