Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL
pro
) ...is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL
pro
. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL
pro
s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.
Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the ...SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.
Abstract
The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for ...developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL
pro
) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL
pro
with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CL
pro
inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.
Polycomb Repressive Complex 2 (PRC2) modulates the chromatin structure and transcriptional repression by trimethylation lysine 27 of histone H3 (H3K27me3), a process that necessitates the ...protein-protein interaction (PPI) between the catalytic subunit EZH2 and EED. Deregulated PRC2 is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. However, until now, there have been no reported small molecule compounds targeting the EZH2-EED interactions. In the present study, we identified astemizole, an FDA-approved drug, as a small molecule inhibitor of the EZH2-EED interaction of PRC2. The disruption of the EZH2-EED interaction by astemizole destabilizes the PRC2 complex and inhibits its methyltransferase activity in cancer cells. Multiple lines of evidence have demonstrated that astemizole arrests the proliferation of PRC2-driven lymphomas primarily by disabling the PRC2 complex. Our findings demonstrate the chemical tractability of the difficult PPI target by a small molecule compound, highlighting the therapeutic promise for PRC2-driven human cancers via targeted destruction of the EZH2-EED complex.
Human inflammatory disease, multiple sclerosis (MS), is a demyelinating disease of central nervous system (CNS). The experimental autoimmune encephalomyelitis (EAE) is the most commonly used as ...experimental model because of its key pathological features’ approximation of MS. The interaction between complex elements in immune system and in the CNS determines the MS pathogenesis. However, there is no cure for MS and the treatment for MS still encounters great challenges. Thus, finding a more effective disease-modifying treatment is imminent. In the present study, we investigated whether 9,10-Anhydrodehydroartemisin (ADART), a compound derived from artemisinin, could decrease demyelination in EAE and the underlying mechanisms. In established EAE mice, 100 mg/kg 9,10-Anhydrodehydroartemisinin (ADART) effectively reduced CNS and peripheral immune system infiltration inflammatory cells including CD4
+
IFN-γ
+
Th1 cells and CD4
+
IL-17A
+
Th17 cells. Correspondingly, the serum level of IFN-γ and IL-17A was also reduced.
In vitro
, ADART almost completely inhibited Th17 differentiation, and partially inhibited Th1 differentiation in 10 μM. This research revealed that ADART could be a great promising avenue among current therapies for MS.
Nowadays, a large number of people in the world are suffering from chronic Hepatitis C. HCV NS5B polymerase conserved across the identified 7 HCV genotypes is considered to be the most promising ...target in combating HCV. During the past decade, significant progress has been made in the discovery of novel nucleoside HCV NS5B polymerase inhibitors. A potent anti-HCV drug, sofosbuvir with high cure rates has been approved. Besides, quite a few nucleoside anti-HCV agents are being evaluated in clinical trials. The purpose of this review is to present recent progress in the development of nucleoside HCV NS5B polymerase inhibitors, focusing on lead compounds that hold great promise for medicinal use and their structure-activity relationships (SARs) in order to provide guidance for future drug design and discovery.
The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. ...Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted MS model. Due to the recently described critical role of platelets in inflammation and autoimmune disease, we examined the relationship between platelets, inflammation, and anxiety-like behavior in EAE. In the elevated plus maze, EAE-induced C57BL/6J mice showed decreased time spent in the open arms relative to vehicle-only controls, demonstrating an increase in anxiety-like behavior. This effect occurred in the presence of platelet⁻neuron association, but absence of lymphocytic infiltration, in the hippocampal parenchyma. Platelet depletion at the pre-clinical disease stage, using antibody-mediated lysis prevented the EAE-induced increase in anxiety-like behavior, while no significant difference in distance moved was recorded. Furthermore, platelet depletion was also associated with reduction of the pro-inflammatory environment to control levels in the hippocampus and prevention of EAE disease symptomology. These studies demonstrate the high efficacy of a platelet-targeting approach in preventing anxiety-like symptoms and clinical manifestations of EAE and have implications for the treatment of neuropsychiatric symptoms in MS.
Energetic heavy ions with short duration can be generated in the interaction of ultrashort ultraintense (USUI) laser pulse with solid matter. However, the energy conversion efficiency from laser to ...heavy ions is usually very low. Herein, a novel scheme for efficient transfer of USUI laser energy to the heavy ions of microscopic dust grains in dusty plasma is proposed. Due to the resulting ultraintense space‐charge field, the heavy ions expand isotropically together with the laser heated and expelled grain electrons as a plasma cloud on roughly the ion acoustic timescale. It is found that with 3.1 × 1020 W cm−2 USUI laser, one can produce hundreds‐megaelectronvolt C6+ ions with ≈60% energy transfer efficiency. In fact, up to 300 GeV Au79+ ions with ≈30% energy transfer efficiency can be obtained by using 8.8 × 1023 W cm−2 laser. This result suggests the possibility of using hundreds‐petawatt laser facility to investigate heavy‐ion collisions for nuclear state detection and quantum cardiodynamics phase transition.
For ultrashort ultraintense laser‐accelerated heavy ions, the energy conversion efficiency is usually very low. Herein, a novel scheme for efficient transfer of laser energy to the heavy ions of microscopic dust grains in dusty plasma is proposed. Due to the isotropic expansion of grain, hundreds‐megaelectronvolt carbon ions with ≈60% efficiency can be produced with 3.1 × 1020 W cm−2 laser.
Previously, from the tannic sumac plant (
), we developed the Rutan 25 mg oral drug tablets with antiviral activity against influenza A and B viruses, adenoviruses, paramyxoviruses, herpes virus, and ...cytomegalovirus. Here, our re-purposing study demonstrated that Rutan at 25, 50, and 100 mg/kg provided a very effective and safe treatment for COVID-19 infection, simultaneously inhibiting two vital enzyme systems of the SARS-CoV-2 virus: 3C-like proteinase (3CLpro) and RNA-dependent RNA polymerase (RdRp). There was no drug accumulation in experimental animals' organs and tissues. A clinical study demonstrated a statistically significant decrease in the C-reactive protein and a reduction of the viremia period. In patients receiving Rutan 25 mg (children) and 100 mg (adults), the frequency of post-COVID-19 manifestations was significantly less than in the control groups not treated with Rutan tablets. Rutan, having antiviral activity, can provide safe treatment and prevention of COVID-19 in adults and children.
ClinicalTrials.gov, ID NCT05862883.
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