Background In the urgent campaign to develop therapeutics against SARS-CoV-2, natural products have been an important source of new lead compounds. Results We herein identified two natural products, ginkgolic acid and anacardic acid, as inhibitors using a high-throughput screen targeting the SARS-CoV-2 papain-like protease (PLpro). Moreover, our study demonstrated that the two hit compounds are dual inhibitors targeting the SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) in addition to PLpro. A mechanism of action study using enzyme kinetics further characterized the two compounds as irreversible inhibitors against both 3CLpro and PLpro. Significantly, both identified compounds inhibit SARS-CoV-2 replication in vitro at nontoxic concentrations. Conclusions Our finding provides two novel natural products as promising SARS-CoV-2 antivirals.
The emerging SARS-CoV-2 infection is the cause of the global COVID-19 pandemic. To date, there are limited therapeutic options available to fight this disease. Here we examined the inhibitory abilities of two broad-spectrum antiviral natural products chebulagic acid (CHLA) and punicalagin (PUG) against SARS-CoV-2 viral replication. Both CHLA and PUG reduced virus-induced plaque formation in Vero-E6 monolayer at noncytotoxic concentrations, by targeting the enzymatic activity of viral 3-chymotrypsin-like cysteine protease (3CL pro ) as allosteric regulators. Our study demonstrates the potential use of CHLA and PUG as novel COVID-19 therapies.
Influenza A virus infections cause significant morbidity and mortality, and novel antivirals are urgently needed. Influenza RNA-dependent RNA polymerase (RdRp) activity has been acknowledged as a promising target for novel antivirals. In this study, a phenotypic versus target-based screening strategy was established to identify the influenza A virus inhibitors targeting the virus RNA transcription/replication steps by sequentially using an RdRp-targeted screen and a replication-competent reporter virus-based approach using the same compounds. To demonstrate the utility of this approach, a pilot screen of a library of 891 compounds derived from natural products was carried out. Quality control analysis indicates that the primary screen was robust for identification of influenza A virus inhibitors targeting RdRp activity. Finally, two hit candidates were identified, and one was validated as a putative RdRp inhibitor. This strategy can greatly reduce the number of false positives and improve the accuracy and efficacy of primary screening, thereby providing a powerful tool for antiviral discovery.
Influenza A virus (IAV) causes great morbidity and mortality worldwide every year. However, there are only a limited number of drugs clinically available against IAV infection. Further, emergence of drug‐resistant strains can render those drugs ineffective. Thus there is an unmet medical need to develop new anti‐influenza agents. In this study, we show that punicalagin from plants possesses strong anti‐influenza activity with a low micromolar IC50 value in tissue culture. Using a battery of bioassays such as single‐cycle replication assay, neuraminidase (NA) inhibition assay, and virus yield reduction assay, we demonstrate that the primary mechanism of action (MOA) of punicalagin is the NA‐mediated viral release. Moreover, punicalagin can inhibit replication of different strains of influenza A and B viruses, including oseltamivir‐resistant virus (NA/H274Y), indicating that punicalagin is a broad spectrum antiviral against both IAV and IBV. Further, although punicalagin targets NA like oseltamivir, it has a different MOA. These results suggest that punicalagin is an influenza NA inhibitor that may be further developed as a novel antiviral against influenza viruses.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19), which threatens human health and public safety. In the urgent campaign to develop anti-SARS-CoV-2 therapies, the initial entry step is one of the most appealing targets. In this review, we summarize the current understanding of SARS-CoV-2 cell entry, and the development of targeted antiviral strategies. Moreover, we speculate upon future directions toward next-generation of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a major public health threat worldwide and emphasizes an urgent need for effective therapeutics.Recently, Ordonez et al. identified sulforaphane (SFN) as a novel coronavirus inhibitor both in vitro and in mice, but the mechanism of action remains elusive. In this study, we independently discovered SFN for its inhibitory effect against SARS-CoV-2 using a target-based screening approach, identifying the viral 3-chymotrypsin-like protease (3CL pro ) as a target of SFN. Mechanistically, SFN inhibits 3CL pro in a reversible, mixed-type manner. Moreover, enzymatic kinetics studies reveal that SFN is a slow-binding inhibitor, following a two-step interaction.Initially, an encounter complex forms by specific binding of SFN to the active pocket of 3CL pro ; subsequently, the isothiocyanate group of SFN as "warhead" reacts covalently to the catalytic cysteine in a slower velocity, stabilizing the SFN-3CL pro complex. Our study has identified a new lead of the covalent 3CL pro inhibitors which has potential to be developed as a therapeutic agent to treat SARS-CoV-2 infection.
This article is aimed to study how climate change affects mangroves and how to prevent them from being damaged by climate change. Nowadays, the climate is becoming more and more unstable, and extreme weather occurs frequently, such as hail in the Tropics. However, the stability of climate is very important for human beings, because climate comes from nature, and nature is the basis of human survival. Therefore, in order to better observe climate change and improve current climate, the mangrove has become the Savior to human, which means that the mangrove is also significant to human beings. While some group of the mangrove have been damaged by climate change. Therefore, this paper will analyze the impact of climate change on mangroves from the perspective of climate factors of acid rain and global warming. The conclusion is that strengthening monitoring and creating more habitats for mangroves may be the appropriate solution. At last, this paper will be useful to cope with climate change better and be helpful for the future research.
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