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1.
Chinese Journal of Parasitology and Parasitic Diseases ; 39(2):245-248, 2021.
Article in Chinese | EMBASE | ID: covidwho-20238636

ABSTRACT

During the COVID-19 epidemic, blood samples are usually processed at 56 to attenuate the virus before pathogen detection. 71 blood samples of malaria patients reported by Shanghai Center for Disease Control and Prevention in 2017-2019 were collected, including 38 with Plasmodium falciparum infection, 8 P. malariae, 11 P. ovale and 14 P. vivax. The effect of inactivation on the thermal stability of P. falciparum histidine rich protein II (PfHRPII) and Plasmodium lactate dehydrogenase (pLDH) in blood samples was assessed before and after incubation at 56 for 30 min using the rapid diagnostic test (RDT) kit. The results showed that among the 38 P. falciparum T1-positive (PfHRPII) blood samples before heat treatment, 35 samples remained to be T1-positive (92.11%, 35/38, chi2=3.123, P>0.05) after heat treatment;while 54 blood samples (26 P. falciparum, 6 P. vivax, 10 P. ovale and 12 P. vivax) that were T2-positive (pLDH) before heat treatment turned to be T2-negative (positive rate 0, 0/54, chi2=87.755, P<0.01) after heat treatment. It was demonstrated that PfHRPII is stable during incubation at 56 for 30 min, while pLDH is unstable and degraded or inactivated during the heating. Therefore, the detection results of P. falciparum will not be affected by RDT, but diagnosis of the parasites other than P. falciparum in blood samples may be missed.Copyright © 2021, National Institute of Parasitic Diseases. All rights reserved.

2.
Mol Cell Proteomics ; 22(7): 100585, 2023 May 25.
Article in English | MEDLINE | ID: covidwho-2328399

ABSTRACT

Histidine-rich glycoprotein (HRG) is a liver-produced protein circulating in human serum at high concentrations of around 125 µg/ml. HRG belongs to the family of type-3 cystatins and has been implicated in a plethora of biological processes, albeit that its precise function is still not well understood. Human HRG is a highly polymorphic protein, with at least five variants with minor allele frequencies of more than 10%, variable in populations from different parts of the world. Considering these five mutations we can theoretically expect 35 = 243 possible genetic HRG variants in the population. Here, we purified HRG from serum of 44 individual donors and investigated by proteomics the occurrence of different allotypes, each being either homozygote or heterozygote for each of the five mutation sites. We observed that some mutational combinations in HRG were highly favored, while others were apparently missing, although they ought to be present based on the independent assembly of these five mutation sites. To further explore this behavior, we extracted data from the 1000 genome project (n ∼ 2500 genomes) and assessed the frequency of different HRG mutants in this larger dataset, observing a prevailing agreement with our proteomics data. From all the proteogenomic data we conclude that the five different mutation sites in HRG are not occurring independently, but several mutations at different sites are fully mutually exclusive, whereas others are highly intwined. Specific mutations do also affect HRG glycosylation. As the levels of HRG have been suggested as a protein biomarker in a variety of biological processes (e.g., aging, COVID-19 severity, severity of bacterial infections), we here conclude that the highly polymorphic nature of the protein needs to be considered in such proteomics evaluations, as these mutations may affect HRG's abundance, structure, posttranslational modifications, and function.

3.
Journal of Physics: Conference Series ; 2485(1):012006, 2023.
Article in English | ProQuest Central | ID: covidwho-2298393

ABSTRACT

The SARS-CoV-2 main protease (Mpro) plays an important role in the viral transcription and replication of the SARS-CoV-2 virus that is causing the Covid-19 pandemic worldwide. Therefore, it represents a very attractive target for drug development for treatment of this disease. It is a cysteine protease because it has in the active site the catalytic dyad composed of cysteine (C145) and histidine (H41). The catalytic site represents the binding site for inhibitors, many of them bind to Mpro with a covalent bond. In this research, structural and physiochemical characteristics of the Mpro binding site are investigated when the ligand 11a is covalently and non-covalently bound. All-atom molecular dynamics (MD) simulations were run for 500 ns at physiological temperature (310 K). It is found that conformations of both the Mpro protein and the ligand are stable during the simulation with covalently bound complex showing stronger stability. When the ligand is covalently bound (its final state), residues that stably interact with the ligand are H41, C145, H163, H164 and E166. The optimal conformation of these residues is stabilized also via the Hbond interactions with the catalytic water present in the Mpro binding site. In the case of the non-covalently bound ligand (state before the covalent bond is formed), the binding site residues retain their conformations similar to the covalent binding site, and they still form Hbonds with the catalytic water, except H41. This residue, instead, adopts a different conformation and looses the Hbond with the catalytic water, leaving more freedom to move to the ligand. We hypothesize that H41 could play a role in guiding the ligand to the optimal position for final covalent bonding. Further analyses are in process to check this hypothesis. These results represent an important basis for studying drug candidates against SARS-CoV-2 by means of computer aided drug design.

4.
Vopr Virusol ; 68(1): 18-25, 2023 03 11.
Article in Russian | MEDLINE | ID: covidwho-2295343

ABSTRACT

INTRODUCTION: Currently, low molecular-weight compounds are being developed as potential inhibitors of CoVs replication, targeting various stages of the replication cycle, such as major protease inhibitors and nucleoside analogs. Viroporins can be alternative protein targets. The aim of this study is to identify antiviral properties of histidine derivatives with cage substituents in relation to pandemic strain SARS-CoV-2 in vitro. MATERIALS AND METHODS: Combination of histidine with aminoadamantane and boron cluster anion [B10H10]2 (compounds IIV) was carried out by classical peptide synthesis. Compound were identified by modern physicochemical methods. Antiviral properties were studied in vitro on a monolayer of Vero E6 cells infected with SARS-CoV-2 (alpha strain) with simultaneous administration of compounds and virus. RESULTS: Derivatives of amino acid histidine with carbocycles and boron cluster were synthesized and their antiviral activity against SARS-CoV-2 was studied in vitro. Histidine derivatives with carbocycles and [B10H10]2 have the ability to suppress virus replication. The solubility of substances in aqueous media can be increased due to formation of hydrochloride or sodium salt. DISCUSSION: 2HCl*H-His-Rim (I) showed some effect of suppressing replication of SARS-CoV-2 at a viral load of 100 doses and concentration 31.2 g/ml. This is explained by the weakly basic properties of compound I. CONCLUSION: The presented synthetic compounds showed moderate antiviral activity against SARS-CoV-2. The obtained compounds can be used as model structures for creating new direct-acting drugs against modern strains of coronaviruses.


Subject(s)
Antiviral Agents , COVID-19 , Animals , Chlorocebus aethiops , Humans , Antiviral Agents/therapeutic use , SARS-CoV-2 , Histidine/pharmacology , Boron/pharmacology , Vero Cells , Virus Replication
5.
BMC Anesthesiol ; 22(1): 232, 2022 07 20.
Article in English | MEDLINE | ID: covidwho-2274767

ABSTRACT

BACKGROUND: Decrease in histidine-rich glycoprotein (HRG) was reported as a cause of dysregulation of the coagulation-fibrinolysis and immune systems, leading to multi-organ failure, and it may be a biomarker for sepsis, ventilator-associated pneumonia, preeclampsia, and coronavirus disease 2019. However, the usefulness of HRG in perioperative management remains unclear. This study aimed to assess the usefulness of HRG as a biomarker for predicting postoperative complications. METHODS: This was a single-center, prospective, observational study of 150 adult patients who were admitted to the intensive care unit after surgery. Postoperative complications were defined as those having a grade II or higher in the Clavien-Dindo classification, occurring within 7 days after surgery. The primary outcome was HRG levels in the patients with and without postoperative complications. The secondary outcome was the ability of HRG, white blood cell, C-reactive protein, procalcitonin, and presepsin to predict postoperative complications. Data are presented as number and median (interquartile range). RESULTS: The incidence of postoperative complications was 40%. The HRG levels on postoperative day 1 were significantly lower in patients who developed postoperative complications (n = 60; 21.50 [18.12-25.74] µg/mL) than in those who did not develop postoperative complications (n = 90; 25.46 [21.05-31.63] µg/mL). The Harrell C-index scores for postoperative complications were HRG, 0.65; white blood cell, 0.50; C-reactive protein, 0.59; procalcitonin, 0.73; and presepsin, 0.73. HRG was independent predictor of postoperative complications when adjusted for age, the presence of preoperative cardiovascular comorbidities, American Society of Anesthesiologists Physical Status Classification, operative time, and the volume of intraoperative bleeding (adjusted hazard ratio = 0.94; 95% confidence interval, 0.90-0.99). CONCLUSIONS: The HRG levels on postoperative day 1 could predict postoperative complications. Hence, HRG may be a useful biomarker for predicting postoperative complications.


Subject(s)
COVID-19 , Procalcitonin , Adult , Biomarkers , C-Reactive Protein , Humans , Intensive Care Units , Lipopolysaccharide Receptors , Peptide Fragments , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Prospective Studies , Proteins
6.
EJHaem ; 4(2): 324-338, 2023 May.
Article in English | MEDLINE | ID: covidwho-2284318

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D-dimers are also commonly elevated despite systemic hypofibrinolysis. To understand these unusual features of coronavirus disease 2019 (COVID-19) coagulopathy, 64 adult patients with SARS-CoV-2 infection (36 moderate and 28 severe) and 16 controls were studied. We evaluated the repertoire of plasma protease inhibitors (Serpins, Kunitz, Kazal, Cystatin-like) targeting the fibrinolytic system: Plasminogen Activator Inhibitor-1 (PAI-1), Tissue Plasminogen Activator/Plasminogen Activator Inhibitor-1 complex (t-PA/PAI-1), α-2-Antiplasmin, Plasmin-α2-Antiplasmin Complex, Thrombin-activatable Fibrinolysis Inhibitor (TAFI)/TAFIa, Protease Nexin-1 (PN-1), and Neuroserpin (the main t-PA inhibitor of the central nervous system). Inhibitors of the common (Antithrombin, Thrombin-antithrombin complex, Protein Z [PZ]/PZ inhibitor, Heparin Cofactor II, and α2-Macroglobulin), Protein C ([PC], Protein C inhibitor, and Protein S), contact (Kallistatin, Protease Nexin-2/Amyloid Beta Precursor Protein, and α-1-Antitrypsin), and complement (C1-Inhibitor) pathways, in addition to Factor XIII, Histidine-rich glycoprotein (HRG) and Vaspin were also investigated by enzyme-linked immunosorbent assay. The association of these markers with disease severity was evaluated by logistic regression. Pulmonary expression of PAI-1 and Neuroserpin in the lungs from eight post-mortem cases was assessed by immunohistochemistry. Results show that six patients (10%) developed thrombotic events, and mortality was 11%. There was no significant reduction in plasma anticoagulants, in keeping with a compensated state. However, an increase in fibrinolysis inhibitors (PAI-1, Neuroserpin, PN-1, PAP, and t-PA/PAI-1) was consistently observed, while HRG was reduced. Furthermore, these markers were associated with moderate and/or severe disease. Notably, immunostains demonstrated overexpression of PAI-1 in epithelial cells, macrophages, and endothelial cells of fatal COVID-19, while Neuroserpin was found in intraalveolar macrophages only. These results imply that the lungs in SARS-CoV-2 infection provide anti-fibrinolytic activity resulting in a shift toward a local and systemic hypofibrinolytic state predisposing to (immuno)thrombosis, often in a background of compensated disseminated intravascular coagulation.

7.
BMC Bioinformatics ; 24(1): 67, 2023 Feb 24.
Article in English | MEDLINE | ID: covidwho-2280689

ABSTRACT

BACKGROUND: Streptococcus pneumoniae (Pneumococcus) has remained a leading cause of fatal infections such as pneumonia, meningitis, and sepsis. Moreover, this pathogen plays a major role in bacterial co-infection in patients with life-threatening respiratory virus diseases such as influenza and COVID-19. High morbidity and mortality in over one million cases, especially in very young children and the elderly, are the main motivations for pneumococcal vaccine development. Due to the limitations of the currently marketed polysaccharide-based vaccines, non-serotype-specific protein-based vaccines have received wide research interest in recent years. One step further is to identify high antigenic regions within multiple highly-conserved proteins in order to develop peptide vaccines that can affect various stages of pneumococcal infection, providing broader serotype coverage and more effective protection. In this study, immunoinformatics tools were used to design an effective multi-epitope vaccine in order to elicit neutralizing antibodies against multiple strains of pneumococcus. RESULTS: The B- and T-cell epitopes from highly protective antigens PspA (clades 1-5) and PhtD were predicted and immunodominant peptides were linked to each other with proper linkers. The domain 4 of Ply, as a potential TLR4 agonist adjuvant candidate, was attached to the end of the construct to enhance the immunogenicity of the epitope vaccine. The evaluation of the physicochemical and immunological properties showed that the final construct was stable, soluble, antigenic, and non-allergenic. Furthermore, the protein was found to be acidic and hydrophilic in nature. The protein 3D-structure was built and refined, and the Ramachandran plot, ProSA-web, ERRAT, and Verify3D validated the quality of the final model. Molecular docking analysis showed that the designed construct via Ply domain 4 had a strong interaction with TLR4. The structural stability of the docked complex was confirmed by molecular dynamics. Finally, codon optimization was performed for gene expression in E. coli, followed by in silico cloning in the pET28a(+) vector. CONCLUSION: The computational analysis of the construct showed acceptable results, however, the suggested vaccine needs to be experimentally verified in laboratory to ensure its safety and immunogenicity.


Subject(s)
COVID-19 , Streptococcus pneumoniae , Child , Humans , Child, Preschool , Aged , Molecular Docking Simulation , Escherichia coli , Toll-Like Receptor 4 , Epitopes, T-Lymphocyte/chemistry , Vaccines, Subunit/chemistry , Vaccines, Subunit/genetics , Epitopes, B-Lymphocyte , Computational Biology/methods
8.
Saudi Pharm J ; 31(2): 228-244, 2023 Feb.
Article in English | MEDLINE | ID: covidwho-2238542

ABSTRACT

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

9.
J Biol Chem ; 299(2): 102790, 2023 02.
Article in English | MEDLINE | ID: covidwho-2238444

ABSTRACT

3-Chymotrypsin-like protease (3CLpro) is a promising drug target for coronavirus disease 2019 and related coronavirus diseases because of the essential role of this protease in processing viral polyproteins after infection. Understanding the detailed catalytic mechanism of 3CLpro is essential for designing effective inhibitors of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular dynamics studies have suggested pH-dependent conformational changes of 3CLpro, but experimental pH profiles of SARS-CoV-2 3CLpro and analyses of the conserved active-site histidine residues have not been reported. In this work, pH-dependence studies of the kinetic parameters of SARS-CoV-2 3CLpro revealed a bell-shaped pH profile with 2 pKa values (6.9 ± 0.1 and 9.4 ± 0.1) attributable to ionization of the catalytic dyad His41 and Cys145, respectively. Our investigation of the roles of conserved active-site histidines showed that different amino acid substitutions of His163 produced inactive enzymes, indicating a key role of His163 in maintaining catalytically active SARS-CoV-2 3CLpro. By contrast, the H164A and H172A mutants retained 75% and 26% of the activity of WT, respectively. The alternative amino acid substitutions H172K and H172R did not recover the enzymatic activity, whereas H172Y restored activity to a level similar to that of the WT enzyme. The pH profiles of H164A, H172A, and H172Y were similar to those of the WT enzyme, with comparable pKa values for the catalytic dyad. Taken together, the experimental data support a general base mechanism of SARS-CoV-2 3CLpro and indicate that the neutral states of the catalytic dyad and active-site histidine residues are required for maximum enzyme activity.


Subject(s)
Biocatalysis , Coronavirus 3C Proteases , Histidine , SARS-CoV-2 , Humans , Histidine/genetics , Histidine/metabolism , Hydrogen-Ion Concentration , SARS-CoV-2/enzymology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Catalytic Domain , Kinetics , Amino Acid Substitution
10.
Int J Mol Sci ; 23(21)2022 Oct 31.
Article in English | MEDLINE | ID: covidwho-2099576

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated type 1 interferon (IFN-1) production, the pathophysiology of which involves sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) tetramerization and the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. As a result, type I interferonopathies are exacerbated. Aspirin inhibits cGAS-mediated signaling through cGAS acetylation. Acetylation contributes to cGAS activity control and activates IFN-1 production and nuclear factor-κB (NF-κB) signaling via STING. Aspirin and dapsone inhibit the activation of both IFN-1 and NF-κB by targeting cGAS. We define these as anticatalytic mechanisms. It is necessary to alleviate the pathologic course and take the lag time of the odds of achieving viral clearance by day 7 to coordinate innate or adaptive immune cell reactions.


Subject(s)
COVID-19 Drug Treatment , Interferon Type I , Humans , Acetylation , NF-kappa B/metabolism , Drug Repositioning , Membrane Proteins/metabolism , SARS-CoV-2 , Nucleotidyltransferases/metabolism , Interferon Type I/metabolism , Aspirin , Immunity, Innate/genetics
11.
Pharmacognosy Magazine ; 18(79):773-782, 2022.
Article in English | EMBASE | ID: covidwho-2066903

ABSTRACT

Background: Tabebuia impetiginosa is an important medicinal plant rich in lapachol, alpha-lapachone, and beta-lapachone known to possess several biological activities. Objective(s): In this study, we investigated the drug potential of lapachol, alpha-lapachone, and beta-lapachone using molecular docking, molecular dynamic (MD), and drug-likeness properties. Material(s) and Method(s): The computational study was performed using SwissADME software for the determination of the pharmacokinetic properties of the tested compounds. AutoDock Vina and Genetic Optimization for Ligand Docking (GOLD) were used for the docking analysis, and MD simulations were run using Schrodinger's Desmond Simulation. Result(s): The three compounds lapachol, alpha-lapachone, and beta-lapachone binds to cysteine (Cys)-histidine (His) catalytic dyad (Cys145 and His41) along with the other residues with, respectively, the following docking score 48.69, 47.06, and 47.79. Against viral entry receptor, human angiotensin-converting enzyme 2 (hACE-2), alpha-lapachone exhibited the highest GOLD Fitness score complex (54.82) followed by lapachol (42.53) and beta-lapachone and hACE-2 (38.74) generating several active sites in the target proteins. A 100 ns MDs simulation study revealed the stable conformation of bioactive compounds within the cavity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of hACE-2 protein and main protease (Mpro). From the dynamic study, it was observed that lapachol was tightly bound with catalytic dyad residue Cys145 of Mpro with more than 40% time of simulation, also post-simulation MM-GBSA binding free energy (DELTAG Bind) revealed the highest energy score (-51.18 +/- 5.14 kcal/mol) among the evaluated complex. Moreover, the absorption, distribution, metabolism, and excretion (ADME) properties demonstrated that the investigated compounds passed the pharmacokinetic and drug-likeness criteria without undesirable effects. Conclusion(s): The computational study highlighted that these compounds could be highly recommended and developed as part of an effective drug against the SARS-CoV-2 virus. Copyright © 2022 Pharmacognosy Magazine.

12.
Drug Development and Delivery ; 22(4):18-23, 2022.
Article in English | Scopus | ID: covidwho-2012508
13.
Europace ; 24(SUPPL 1), 2022.
Article in English | EMBASE | ID: covidwho-1912823

ABSTRACT

The proceedings contain 629 papers. The topics discussed include: digitalized ECG measure of p-wave duration predicts incident heart failure;diagnostic value of Peguero Lo Presti Electrocardiografic index for diagnosis of left ventricle hypertrophy in correlation with cardiovascular magnetic resonance;electrocardiography: an useful tool for prediction of the diagnosis and severity of pulmonary embolism;association between excessive supraventricular ectopic activity and future diagnosis of atrial fibrillation in patients with cryptogenic stroke;low-level vagus nerve stimulation during cardiac surgery: smart neuromodulation;a polymorphism in histidine-rich calcium binding protein as second hit in phospholamban cardiomyopathy;genetic predisposition according to the age at the onset of atrial fibrillation;familial clustering of unexplained heart failure - a Danish nationwide cohort study;and fever following covid-19 vaccination in subjects with Brugada syndrome: incidence and management.

14.
J Pharmacol Sci ; 150(1): 9-20, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1885946

ABSTRACT

In 2016, sepsis was newly defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis remains one of the crucial medical problems to be solved worldwide. Although the world health organization has made sepsis a global health priority, there remain no specific and effective therapy for sepsis so far. Indeed, over the previous decades almost all attempts to develop novel drugs have failed. This may be partly ascribable to the multifactorial complexity of the septic cascade and the resultant difficulties of identifying drug targets. In addition, there might still be missing links among dysregulated host responses in vital organs. In this review article, recent advances in understanding of the complex pathophysiology of sepsis are summarized, with a focus on neutrophil extracellular traps (NETs), the significant role of NETs in thrombosis/embolism, and the functional roles of plasma proteins, histidine-rich glycoprotein (HRG) and inter-alpha-inhibitor proteins (IAIPs). The specific plasma proteins that are markedly decreased in the acute phase of sepsis may play important roles in the regulation of blood cells, vascular endothelial cells and coagulation. The accumulating evidence may provide us with insights into a novel aspect of the pathophysiology of sepsis and septic ARDS, including that in COVID-19.


Subject(s)
COVID-19 , Extracellular Traps , Sepsis , Blood Proteins/metabolism , Endothelial Cells/metabolism , Extracellular Traps/metabolism , Glycoproteins/metabolism , Humans , Neutrophils
15.
J Gene Med ; 24(5): e3415, 2022 05.
Article in English | MEDLINE | ID: covidwho-1669502

ABSTRACT

Gene therapy has emerged as a promising tool for treating different intractable diseases, particularly cancer or even viral diseases such as COVID-19 (coronavirus disease 2019). In this context, various non-viral gene carriers are being explored to transfer DNA or RNA sequences into target cells. Here, we review the applications of the naturally occurring amino acid histidine in the delivery of nucleic acids into cells. The biocompatibility of histidine-enhanced gene delivery systems has encouraged their wider use in gene therapy. Histidine-based gene carriers can involve the modification of peptides, dendrimers, lipids or nanocomposites. Several linear polymers, such as polyethylenimine, poly-l-lysine (synthetic) or dextran and chitosan (natural), have been conjugated with histidine residues to form complexes with nucleic acids for intracellular delivery. The challenges, opportunities and future research trends of histidine-based gene deliveries are investigated.


Subject(s)
COVID-19 , Nucleic Acids , COVID-19/therapy , Gene Transfer Techniques , Histidine/genetics , Humans , Transfection
16.
Chinese Journal of Parasitology and Parasitic Diseases ; 39(2):245-248, 2021.
Article in Chinese | Scopus | ID: covidwho-1600029

ABSTRACT

During the COVID-19 epidemic, blood samples are usually processed at 56 ℃ to attenuate the virus before pathogen detection. 71 blood samples of malaria patients reported by Shanghai Center for Disease Control and Prevention in 2017-2019 were collected, including 38 with Plasmodium falciparum infection, 8 P. malariae, 11 P. ovale and 14 P. vivax. The effect of inactivation on the thermal stability of P. falciparum histidine rich protein Ⅱ (PfHRPⅡ) and Plasmodium lactate dehydrogenase (pLDH) in blood samples was assessed before and after incubation at 56 ℃ for 30 min using the rapid diagnostic test (RDT) kit. The results showed that among the 38 P. falciparum T1-positive (PfHRPⅡ) blood samples before heat treatment, 35 samples remained to be T1-positive (92.11%, 35/38, χ2=3.123, P>0.05) after heat treatment;while 54 blood samples (26 P. falciparum, 6 P. vivax, 10 P. ovale and 12 P. vivax) that were T2-positive (pLDH) before heat treatment turned to be T2-negative (positive rate 0, 0/54, χ2=87.755, P<0.01) after heat treatment. It was demonstrated that PfHRPⅡ is stable during incubation at 56 ℃ for 30 min, while pLDH is unstable and degraded or inactivated during the heating. Therefore, the detection results of P. falciparum will not be affected by RDT, but diagnosis of the parasites other than P. falciparum in blood samples may be missed. © 2021, National Institute of Parasitic Diseases. All rights reserved.

17.
mBio ; 12(4): e0178121, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1349195

ABSTRACT

The 2',5'-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2',5'-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses (CoVs) and rotaviruses encode 2-5A-degrading enzymes, thereby antagonizing RNase L and its antiviral effects. A-kinase-anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self-double-stranded RNAs that activate OAS. We show that these enzymes, members of the two-histidine phosphoesterase (2H-PE) superfamily, constitute a subfamily referred here as 2',5'-PEs. 2',5'-PEs from the mouse CoV mouse hepatitis virus (MHV) (NS2), Middle East respiratory syndrome coronavirus (MERS-CoV) (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3',5'-oligoribonucleotides, they all cleaved 2',5'-oligoadenylates efficiently but with variable activity against other 2',5'-oligonucleotides. The 2',5'-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2',5'-p3A3) producing mono- or diadenylates with 2',3'-cyclic phosphate termini. Our results suggest that the elimination of 2-5A might be the sole function of viral 2',5'-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L. IMPORTANCE Viruses often encode accessory proteins that antagonize the host antiviral immune response. Here, we probed the evolutionary relationships and biochemical activities of two-histidine phosphoesterases (2H-PEs) that allow some coronaviruses and rotaviruses to counteract antiviral innate immunity. In addition, we investigated the mammalian enzyme AKAP7, which has homology and shared activities with the viral enzymes and might reduce self-injury. These viral and host enzymes, which we refer to as 2',5'-PEs, specifically degrade 2',5'-oligoadenylate activators of the antiviral enzyme RNase L. We show that the host and viral enzymes are metal ion independent and exclusively cleave 2',5'- and not 3',5'-phosphodiester bonds, producing cleavage products with cyclic 2',3'-phosphate termini. Our study defines 2',5'-PEs as enzymes that share characteristic conserved features with the 2H-PE superfamily but have specific and distinct biochemical cleavage activities. These findings may eventually lead to pharmacological strategies for developing antiviral drugs against coronaviruses, rotaviruses, and other viruses.


Subject(s)
A Kinase Anchor Proteins/metabolism , Adenine Nucleotides/metabolism , Endoribonucleases/metabolism , Middle East Respiratory Syndrome Coronavirus/enzymology , Murine hepatitis virus/enzymology , Oligoribonucleotides/metabolism , Rotavirus/enzymology , Animals , Humans , Immunity, Innate/immunology , Interferons/immunology , Mice
18.
Curr Res Pharmacol Drug Discov ; 2: 100045, 2021.
Article in English | MEDLINE | ID: covidwho-1351596

ABSTRACT

Remdesivir, a monophosphate prodrug of nucleoside analog GS-441524, is widely used for the treatment of moderate to severe COVID-19. It has been suggested to use GS-441524 instead of remdesivir in the clinic and in new inhalation formulations. Thus, we compared the anti-SARS-CoV-2 activity of remdesivir and GS-441524 in Vero E6, Vero CCL-81, Calu-3, Caco-2 â€‹cells, and anti-HCoV-OC43 activity in Huh-7 â€‹cells. We also compared the cellular pharmacology of these two compounds in Vero E6, Vero CCL-81, Calu-3, Caco-2, Huh-7, 293T, BHK-21, 3T3 and human airway epithelial (HAE) cells. Overall, remdesivir exhibited greater potency and superior intracellular metabolism than GS-441524 except in Vero E6 and Vero CCL-81 â€‹cells.

19.
Phytomed Plus ; 1(4): 100083, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1253471

ABSTRACT

Background: Lack of treatment of novel Coronavirus disease led to the search of specific antivirals that are capable to inhibit the replication of the virus. The plant kingdom has demonstrated to be an important source of new molecules with antiviral potential. Purpose: The present study aims to utilize various computational tools to identify the most eligible drug candidate that have capabilities to halt the replication of SARS-COV-2 virus by inhibiting Main protease (Mpro) enzyme. Methods: We have selected plants whose extracts have inhibitory potential against previously discovered coronaviruses. Their phytoconstituents were surveyed and a library of 100 molecules was prepared. Then, computational tools such as molecular docking, ADMET and molecular dynamic simulations were utilized to screen the compounds and evaluate them against Mpro enzyme. Results: All the phytoconstituents showed good binding affinities towards Mpro enzyme. Among them laurolitsine possesses the highest binding affinity i.e. -294.1533 kcal/mol. On ADMET analysis of best three ligands were simulated for 1.2 ns, then the stable ligand among them was further simulated for 20 ns. Results revealed that no conformational changes were observed in the laurolitsine w.r.t. protein residues and low RMSD value suggested that the Laurolitsine-protein complex was stable for 20 ns. Conclusion: Laurolitsine, an active constituent of roots of Lindera aggregata, was found to be having good ADMET profile and have capabilities to halt the activity of the enzyme. Therefore, this makes laurolitsine a good drug candidate for the treatment of COVID-19.

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