The Natural Stilbenoid (-)-Hopeaphenol Inhibits Cellular Entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7, and B.1.351 Variants.

Antivirals are urgently needed to combat the global SARS-CoV-2/COVID-19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host angiotensin-converting enzyme II (ACE2) receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here, we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (-)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (-)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 µM, in contrast to an IC50 of 28.3 µM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index, 257.3). When assessed against the USA-WA1/2020 variant, (-)-hopeaphenol also inhibited entry of a VSVΔG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect and yield reduction assays (50% effective concentrations [EC50s], 10.2 to 23.4 µM) without cytotoxicity and approaching the activities of the control antiviral remdesivir (EC50s, 1.0 to 7.3 µM). Notably, (-)-hopeaphenol also inhibited two emerging variants of concern, B.1.1.7/Alpha and B.1.351/Beta in both viral and spike-containing pseudovirus assays with similar or improved activities over the USA-WA1/2020 variant. These results identify (-)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants of concern.

Design, synthesis and screening of a drug discovery library based on an Eremophila-derived serrulatane scaffold.

Chemical studies of the aerial parts of the Australian desert plant Eremophila microtheca afforded the targeted and known diterpenoid scaffolds, 3,7,8-trihydroxyserrulat-14-en-19-oic acid and 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid. The most abundant serrulatane scaffold was converted to the poly-methyl derivatives, 3-hydroxy-7,8-dimethoxyserrulat-14-en-19-oic acid methyl ester and 3,7,8-trimethoxyserrulat-14-en-19-oic acid methyl ester using simple and rapid methylation conditions consisting of DMSO, NaOH and MeI at room temperature. Subsequently a 12-membered amide library was synthesised by reacting the methylated scaffolds with a diverse series of commercial primary amines. The chemical structures of the 12 undescribed semi-synthetic analogues were fully characterised following 1D/2D NMR, MS, UV, ECD and [α]D data analyses. All compounds were evaluated for their anthelmintic, anti-microbial and anti-viral activities. While none of the compounds significantly inhibited motility or development of the exsheathed third-stage larvae (xL3s) of a pathogenic ruminant parasite, Haemonchus contortus, the tri-methylated analogue induced a skinny phenotype in fourth-stage larvae (L4s) after seven days of treatment (IC50 = 14 µM). Anti-bacterial and anti-fungal activities were not observed at concentrations up to 20 µM. Activity against HIV latency reversal was tested in inducible, chronically-infected cells, with the tri-methylated analogue being the most active (EC50 = 38 µM).

Comparison of Microchip Transponder and Noncontact Infrared Thermometry with Rectal Thermometry in Domestic Swine (Sus scrofa domestica).

During disease outbreaks, core temperature is a useful health metric in swine, due to the presence of pyrexia especially during the acute phase of infection. Despite technologic advances in other facets of swine production and health management, rectal thermometry continues to be the 'gold standard' for measuring core body temperature. However, for various reasons, collecting rectal temperatures can be difficult and unsafe depending on the housing modality. In addition, the delay between insertion of the rectal thermometer and obtaining a reading can affect measurement accuracy, especially when the pig requires physical restraint. Clearly safer, faster, and more accurate and precise temperature acquisition methods that necessitate minimal or no handling of swine are needed. We therefore compared rectal thermometers, subcutaneous microchips, and an inexpensive handheld infrared thermometer by measuring the core body temperature of 24 male castrated piglets at random intervals over a 5-wk period. The core body temperature (mean ± 1 SD) was 39.3±0.5 °C by rectal thermometry, 39.0±0.7 °C by microchip transponder, and 34.3±1.0 °C by infrared thermometry; these 3 values differed significantly. Although the readings obtain by using infrared thermometry were numerically lower than those from the other methods, it is arguably the safest method for assessing the core temperature of swine and showed strong relative correlation with rectal temperature.