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Brilacidin, a mimetic of host defense peptides (HDPs), is currently in Phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by inactivating the virus. In this study, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on the host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, an HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on the host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.

Red-soil sloping farmland in southern China plays a crucial role in the local economy and food production. However, improper tillage practices have resulted in topsoil degradation and deteriorating soil quality. This study investigated changes in soil physico-chemical properties under four tillage methods—cross-slope ridge tillage (RT), down-slope ridge tillage (DT), plastic mulching (PM), and conventional tillage (CT)—on red-soil sloping farmland. The study applied the Soil Management Assessment Framework (SMAF) to assess the influence of these tillage practices on soil quality. Results indicated that PM can increase the total porosity of the soil, reduce soil bulk density, and simultaneously decrease soil surface-water evaporation, significantly improving the soil's water-retention capacity. RT improved soil aggregate formation and stability, leading to increased macro-aggregate content, mean weight diameter, and soil water-stable aggregate stability rates. PM and RT effectively preserved soil nutrients like total nitrogen and organic matter, although PM lowered soil pH, potentially causing acidification. RT demonstrated the highest soil quality, with PM following. Crop growth positively impacted soil macro-aggregate content and stability, showing continuous improvement in soil structure and quality (p < 0.05). Priority should be given to RT in red-soil sloping farmland, followed by PM and CT, while avoiding DT if possible. This research furnishes valuable scientific substantiation for the selection of optimal tillage practices in the preservation of soil quality on red-soil slopes. [ABSTRACT FROM AUTHOR]

Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target. Guided by molecular dynamics simulations, we previously designed first-in-class M2-V27A inhibitors. One of the potent lead compounds, spiroadamantane amine (3), inhibits both the M2-WT and M2-V27A mutant with IC50 values of 18.7 and 0.3 μM, respectively, in in vitro electrophysiological assays. Encouraged by these findings, in this study we further examine the in vitro and in vivo antiviral activity of compound 3 in inhibiting both amantadine-sensitive and -resistant influenza A viruses. Compound 3 not only had single to sub-micromolar EC50 values against M2-WT- and M2-V27A-containing influenza A viruses in antiviral assays, but also rescued mice from lethal viral infection by either M2-WT- or M2-V27A-containing influenza A viruses. In addition, we report the design of two analogs of compound 3, and one was found to have improved in vitro antiviral activity over compound 3. Collectively, this study represents the first report demonstrating the in vivo antiviral efficacy of inhibitors targeting M2 mutants. The results suggest that inhibitors targeting drug-resistant M2 mutants are promising antiviral drug candidates worthy of further development.

The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as an approximation for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays identified substitutions which conferred strong nirmatrelvir resistance and others that compromised activity. On the other hand, N142A and the P132H mutation, carried by the Omicron variant, caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used. Author summary: The SARS-CoV-2 virus has proven to be highly adept at evading the newly developed vaccines. Antiviral drugs provide an important alternative that can reduce disease severity. Nirmatrelvir, an orally available drug approved by the FDA to treat COVID-19, inhibits the SARS-CoV-2 main or 3C-like protease (Mpro or 3CLpro) and reduces the severity of COVID-19 infections. However, continued use of nirmatrelvir will likely drive the emergence of drug resistant Mpro mutations. Our study reports a rapid, inexpensive, and non-pathogenic system using baker's yeast that can determine if potential Mpro mutations may confer drug resistance. Furthermore, we solve the structures of two Mpro mutants first characterized in yeast that provide insights into how E166 can change to drive resistance versus leading to inactivity. Our results can aid in advancing our understanding of resistance mechanisms that will be important as nirmatrelvir and other protease inhibitors become more widely used. [ABSTRACT FROM AUTHOR]