Comprehensive Overview of Diamide Derivatives Acting as Ryanodine Receptor Activators.

The world's hunger is continuously rising due to conflicts, climate change, pandemics (such as the recent COVID-19), and crop pests and diseases. It is widely accepted that zero hunger is impossible without using agrochemicals to control crop pests and diseases. Diamide insecticides are one of the widely used green insecticides developed in recent years and play important roles in controlling lepidopteran pests. Currently, eight diamine insecticides have been commercialized, which target the insect ryanodine receptors. This review summarizes the development and optimization processes of diamide derivatives acting as ryanodine receptor activators. The review also discusses pest resistance to diamide derivatives and possible solutions to overcome the limitations posed by the resistance. Thus, with reference to structural biology, this study provides an impetus for designing and developing diamide insecticides with improved insecticidal activities.

Tranilast as an Adjunctive Therapy in Hospitalized Patients with Severe COVID- 19: A Randomized Controlled Trial.

BACKGROUND: Tranilast is a potential NLRP3 inflammasome inhibitor that may relieve progressive inflammation due to COVID-19. AIM OF THE STUDY: To evaluate the therapeutic effects of Tranilast in combination with antiviral drugs in non-ICU-admitted hospitalized patients with COVID-19. METHODS: This study was an open-label clinical trial that included 72 hospitals admitted patients with severe COVID-19 at Razi Hospital, Ahvaz, Iran, from July 2020-August 2020. These patients were randomly assigned in a 1:1 ratio to control (30) and intervention groups (30). Patients in the control group received antiviral therapy, while patients in the intervention group received Tranilast (300 mg daily) in addition to the antiviral drugs for Seven days. The collected data, including the expression of inflammatory cytokine, laboratory tests, and clinical findings, was used for intragroup comparisons. RESULTS: The intervention group showed significantly lower levels of NLR (p = 0.001), q-CRP (p = 0.002), IL-1 (p = 0.001), TNF (p = 0.001), and LDH (p = 0.046) in comparison with the control group. The effect of intervention was significant in increasing the o2 saturation (F = 7.72, p = 0.007). Long hospitalization (four days or above) was 36.6% in the Tranilast and 66.6% in the control group (RR = 0.58; 95% CI: 0.38-1.06, p = 0.045). In the Tranilst and control groups, one and four deaths or hospitalization in ICU were observed respectively (RR = 0.31; 95% CI: 0.03-2.88, p = 0.20). CONCLUSIONS: Tranilast might be used as an effective and safe adjuvant therapy and enhance the antiviral therapy's efficacy for managing patients with COVID-19.

Synthesis, structural analysis, and docking studies with SARS-CoV-2 of a trinuclear zinc complex with N-phenylanthranilic acid ligands.

The structure of a trinuclear zinc complex, hexakis(µ2-2-anilinobenzoato)diaquatrizinc(II), [Zn2(C13H10NO2)6(H2O)2] or (NPA)6Zn3(H2O)2 (NPA is 2-anilinobenzoate or N-phenylanthranilate), is reported. The complex crystallizes in the triclinic space group P-1 and the central ZnII atom is located on an inversion center. The NPA ligand is found to coordinate via the carboxylate O atoms with unique C-O bond lengths that support an unequal distribution of resonance over the carboxylate fragment. The axial H2O ligands form hydrogen bonds with neighboring molecules that stabilize the supramolecular system in rigid straight chains, with an angle of 180° along the c axis. π stacking is the primary stabilization along the a and b axes, resulting in a highly ordered supramolecular structure. Docking studies show that this unique supramolecular structure of a trinuclear zinc complex has potential for binding to the main protease (Mpro) in SARS-CoV-2 in a different location from Remdesivir, but with a similar binding strength.

Anthranilamides with quinoline and ß-carboline scaffolds: design, synthesis, and biological activity.

In the present study, we report the design and synthesis of novel amide-type hybrid molecules based on anthranilic acid and quinoline or ß-carboline heterocyclic scaffolds. Three types of biological screenings were performed: (i) in vitro antiproliferative screening against a panel of solid tumor and leukemia cell lines, (ii) antiviral screening against several RNA viruses, and (iii) anti-quorum sensing screening using gram-negative Chromobacterium violaceum as the reporter strain. Antiproliferative screening revealed a high activity of several compounds. Anthranilamides 12 and 13 with chloroquine core and halogenated anthranilic acid were the most active agents toward diverse cancer cell lines such as glioblastoma, pancreatic adenocarcinoma, colorectal carcinoma, lung carcinoma, acute lymphoblastic, acute myeloid, chronic myeloid leukemia, and non-Hodgkin lymphoma, but also against noncancerous cell lines. Boc-protected analogs 2 and 3 showed moderate activities against the tested cancer cells without toxic effects against noncancerous cells. A nonhalogenated quinoline derivative 10 with N-benzylanthranilic acid residue was equally active as 12 and 13 and selective toward tumor cells. Chloroquine and quinoline anthranilamides 10-13 exerted pronounced antiviral effect against human coronaviruses 229E and OC43, whereas 12 and 13 against coronavirus OC43 (EC50 values in low micromolar range; selectivity indices from 4.6 to > 10.4). Anthranilamides 14 and 16 with PQ core inhibited HIV-1 with EC50 values of 9.3 and 14.1 µM, respectively. Compound 13 displayed significant anti-quorum/biofilm effect against the quorum sensing reporter strain (IC50 of 3.7 µM) with no apparent bactericidal effect.

Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients.

Cancer patients are particularly susceptible to the development of severe Covid-19, prompting us to investigate the serum metabolome of 204 cancer patients enrolled in the ONCOVID trial. We previously described that the immunosuppressive tryptophan/kynurenine metabolite anthranilic acid correlates with poor prognosis in non-cancer patients. In cancer patients, we observed an elevation of anthranilic acid at baseline (without Covid-19 diagnosis) and no further increase with mild or severe Covid-19. We found that, in cancer patients, Covid-19 severity was associated with the depletion of two bacterial metabolites, indole-3-proprionate and 3-phenylproprionate, that both positively correlated with the levels of several inflammatory cytokines. Most importantly, we observed that the levels of acetylated polyamines (in particular N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine), alone or in aggregate, were elevated in severe Covid-19 cancer patients requiring hospitalization as compared to uninfected cancer patients or cancer patients with mild Covid-19. N1-acetylspermidine and N1,N8-diacetylspermidine were also increased in patients exhibiting prolonged viral shedding (>40 days). An abundant literature indicates that such acetylated polyamines increase in the serum from patients with cancer, cardiovascular disease or neurodegeneration, associated with poor prognosis. Our present work supports the contention that acetylated polyamines are associated with severe Covid-19, both in the general population and in patients with malignant disease. Severe Covid-19 is characterized by a specific metabolomic signature suggestive of the overactivation of spermine/spermidine N1-acetyl transferase-1 (SAT1), which catalyzes the first step of polyamine catabolism.

Tranilast: a potential anti-Inflammatory and NLRP3 inflammasome inhibitor drug for COVID-19.

SARS-CoV-2 is a type of beta-CoV that develops acute pneumonia, which is an inflammatory condition. A cytokine storm has been recognized as one of the leading causes of death in patients with COVID-19. ALI and ARDS along with multiple organ failure have also been presented as the consequences of acute inflammation and cytokine storm. It has been previously confirmed that SARS-CoV, as another member of the beta-CoV family, activates NLRP3 inflammasome and consequently develops acute inflammation in a variety of ways through having complex interactions with the host immune system using structural and nonstructural proteins. Numerous studies conducted on Tranilast have further demonstrated that the given drug can act as an effective anti-chemotactic factor on controlling inflammation, and thus, it can possibly help the improvement of the acute form of COVID-19 by inhibiting some key inflammation-associated transcription factors such as NF-κB and impeding NLRP3 inflammasome. Several studies have comparably revealed the direct effect of this drug on the prevention of inappropriate tissue's remodeling; inhibition of neutrophils, IL-5, and eosinophils; repression of inflammatory cell infiltration into inflammation site; restriction of factors involved in acute airway inflammation like IL-33; and suppression of cytokine IL-13, which increase mucosal secretions. Therefore, Tranilast may be considered as a potential treatment for patients with the acute form of COVID-19 along with other drugs.

SARS-CoV-2 infection: NLRP3 inflammasome as plausible target to prevent cardiopulmonary complications?

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome has recently become an intriguing target of several chronic and viral diseases. Here, we argue that targeting NLRP3 inflammasome could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 infection. We discuss the rationale for NLRP3 targeting in clinical trials as an effective therapeutic strategy aimed to improve prognosis of COVID-19, analyzing the potential of two therapeutic options (tranilast and OLT1177) currently available in clinical practice.

Viruses harness YxxØ motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target.

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.