Efficacy and safety of levetiracetam vs. oxcarbazepine in the treatment of children with epilepsy: a systematic review and meta-analysis.

Background: Levetiracetam (LEV) and oxcarbazepine (OXC) are new antiseizure medications (ASMs). In recent years, OXC monotherapy is widely used in children with epilepsy; however, no consensus exists on applying LEV monotherapy among children with epilepsy. Objective: The present work focused on comparing the efficacy and safety of LEV and OXC monotherapy in treating children with epilepsy. Methods: We conducted a comprehensive search across multiple databases including PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang Database, VIP, and China Biology Medicine disc, covering studies from inception to August 26, 2023. We included randomized controlled trials (RCTs) and cohort studies evaluating the efficacy and safety of LEV and OXC monotherapy for treating epilepsy in children. We utilized Cochrane Risk of Bias Tool in RevMan 5.3 software for assessing included RCTs quality. In addition, included cohort studies quality was determined using Newcastle-Ottawa Scale (NOS). A random-effects model was utilized to summarize the results. Results: This meta-analysis included altogether 14 studies, including 893 children with epilepsy. LEV and OXC monotherapy was not statistical different among children with epilepsy in seizure-free rate (relative risk [RR] = 1.010, 95% confidence interval [CI] [0.822, 1.242], P > 0.05) and seizure frequency decrease of ≥50% compared with baseline [RR = 0.938, 95% CI (0.676, 1.301), P > 0.05]. Differences in total adverse reaction rate [RR = 1.113, 95% CI (0.710, 1.744), P > 0.05] and failure rate because of serious adverse reaction [RR = 1.001, 95% CI (0.349, 2.871), P > 0.05] were not statistical different between LEV and OXC treatments among children with epilepsy. However, the effects of OXC monotherapy on thyroid among children with epilepsy was statistically correlated than that of LEV (thyroid stimulating hormone: standardized mean difference [SMD] = -0.144, 95% CI [-0.613, 0.325], P > 0.05; free thyroxine: SMD = 1.663, 95% CI [0.179, 3.147], P < 0.05). Conclusion: The efficacy of LEV and OXC monotherapy in treating children with epilepsy is similar. However, OXC having a more significant effect on the thyroid than that of LEV. Therefore, LEV may be safer for children with epilepsy who are predisposed to thyroid disease than OXC. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42024514016).

Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors.

Dengue virus (DENV) is a major mosquito-borne human pathogen in tropical countries; however, there are currently no targeted antiviral treatments for DENV infection. Compounds 27 and 29 have been reported to be allosteric inhibitors of DENV RdRp with potent inhibitory effects. In this study, the structures of compounds 27 and 29 were optimized using computer-aided drug design (CADD) approaches. Nine novel compounds were synthesized based on rational considerations, including molecular docking scores, free energy of binding to receptor proteins, predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) parameters, structural diversity, and feasibility of synthesis. Subsequently, the anti-DENV activity was assessed. In the cytopathic effect (CPE) assay conducted on BHK-21 cells using the DENV2 NGC strain, both SW-b and SW-d demonstrated comparable or superior activity against DENV2, with IC50 values of 3.58 ± 0.29 µM and 23.94 ± 1.00 µM, respectively, compared to that of compound 27 (IC50 = 19.67 ± 1.12 µM). Importantly, both SW-b and SW-d exhibited low cytotoxicity, with CC50 values of 24.65 µmol and 133.70 µmol, respectively, resulting in selectivity indices of 6.89 and 5.58, respectively. Furthermore, when compared to the positive control compound 3'-dATP (IC50 = 30.09 ± 8.26 µM), SW-b and SW-d displayed superior inhibitory activity in an enzyme inhibitory assay, with IC50 values of 11.54 ± 1.30 µM and 13.54 ± 0.32 µM, respectively. Molecular dynamics (MD) simulations elucidated the mode of action of SW-b and SW-d, highlighting their ability to enhance π-π packing interactions between benzene rings and residue W795 in the S1 fragment, compared to compounds 27 and 29. Although the transacylsulphonamide fragment reduced the interaction between T794 and NH, it augmented the interaction between R729 and T794. In summary, our study underscores the potential of SW-b and SW-d as allosteric inhibitors targeting the DENV NS5 RdRp domain. However, further in vivo studies are warranted to assess their pharmacology and toxicity profiles.

Safety and efficacy of hyaluronic acid injectable filler in the treatment of nasolabial fold wrinkle: a randomized, double-blind, self-controlled clinical trial.

INTRODUCTION: The injectable skin fillers available for soft tissue augmentation are constantly growing, providing esthetic surgeons with more options in the treatment of scars, lines, and wrinkles. Hyaluronic acid (HA)-derived injectable fillers are ideal to reduce the appearance of nasolabial folding. This study investigated the efficacy and safety of the commercially available HA filler from Maxigen Biotech Inc. (MBI-FD) in the treatment of nasolabial folds (NLFs). METHODS: We analyzed 1,4-butanediol diglycidyl ether (BDDE) residues and injection force test and observed the protein content in MBI-FD, and then was cultured in fibroblast L929 cells and examined for cytotoxicity. Finally, 95 healthy participants underwent dermal filler injection therapy to evaluate the efficacy and safety for 24 and 52 weeks, respectively. RESULTS: BDDE residues in MBI-FD was <0.125 µg/mL. MBI-FD was fitted using 27- and 30-G injection needles with an average pushing force of 14.30 ± 2.07 and 36.43 ± 3.11 N, respectively. Sodium hyaluronate protein in MBI-FD was 7.19 µg/g. The cell viabilities of 1× and 0.5× MBI-FD were 83.25% ± 3.58% and 82.23% ± 1.85%, respectively, indicating MBI-FD had no cytotoxicity, and decreased NLF wrinkles with no serious adverse events. CONCLUSION: MBI-FD is an effective filler for tissue augmentation of the NLFs and may be a suitable candidate as an injectable dermal filler for tissue augmentation in humans in the future.

Virtual screening-based discovery of AI-2 quorum sensing inhibitors that interact with an allosteric hydrophobic site of LsrK and their functional evaluation.

Introduction: Quorum sensing (QS) is a bacterial intracellular and intercellular communication system that regulates virulence factor production, biofilm formation, and antibiotic sensitivity. Quorum-sensing inhibitors (QSIs) are a novel class of antibiotics that can effectively combat antibiotic resistance. Autoinducer-2 (AI-2) is a universal signaling molecule that mediates inter- and intraspecies QS systems among different bacteria. Furthermore, LsrK plays an important role in regulating the activity and stability of the intracellular AI-2 signaling pathway. Thus, LsrK is considered an important target for the development of QSIs. Methods: We designed a workflow integrating molecular dynamic (MD) simulations, virtual screening, LsrK inhibition assays, cell-based AI-2-mediated QS interference assays, and surface plasmon resonance (SPR)-based protein affinity assays to screen for potential LsrK kinase inhibitors. Results: MD simulation results of the LsrK/ATP complex revealed hydrogen bonds and salt bridge formation among four key residues, namely, Lys 431, Tyr 341, Arg 319, and Arg 322, which are critical for the binding of ATP to LsrK. Furthermore, MD simulation results indicated that the ATP-binding site has an allosteric pocket that can become larger and be occupied by small molecule compounds. Based on these MD simulation results, a constraint of forming at least one hydrogen bond with Arg 319, Arg 322, Lys 431, or Tyr 341 residues was introduced when performing virtual screening using Glide's virtual screening workflow (VSW). In the meantime, compounds with hydrophobic group likely to interact with the allosteric hydrophobic pocket are preferred when performing visual inspection. Seventy-four compounds were selected for the wet laboratory assays based on virtual screening and the absorption, distribution, metabolism, and excretion (ADME) properties of these compounds. LsrK inhibition assays revealed 12 compounds inhibiting LsrK by more than 60% at a 200 µM concentration; four of these (Y205-6768, D135-0149, 3284-1358, and N025-0038) had IC50 values below 50 µM and were confirmed as ATP-competitive inhibitors. Six of these 12 LsrK inhibitors exhibited high AI-2 QS inhibition, of which, Y205-6768 had the highest activity with IC50 = 11.28 ± 0.70 µM. The SPR assay verified that compounds Y205-6768 and N025-0038 specifically bound to LsrK. MD simulation analysis of the docking complexes of the four active compounds with LsrK further confirmed the importance of forming hydrogen bonds and salt bridges with key basic amino acid residues including Lys 431, Tyr 341, Arg 319, and Arg 322 and filling the allosteric hydrophobic pocket next to the purine-binding site of LsrK. Discussion: Our study clarified for the first time that there is an allosteric site near the ATP-binding site of Lsrk and that it enriches the structure-activity relationship information of Lsrk inhibitors. The four identified compounds showed novel structures, low molecular weights, high activities, and novel LsrK binding modes, rendering them suitable for further optimization for effective AI-2 QSIs. Our work provides a valuable reference for the discovery of QSIs that do not inhibit bacterial growth, thereby avoiding the emergence of drug resistance.

Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein-Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation.

Quorum sensing (QS) is a cell-to-cell communication mechanism that regulates bacterial pathogenicity, biofilm formation, and antibiotic sensitivity. Among the identified quorum sensing, AI-2 QS exists in both Gram-negative and Gram-positive bacteria and is responsible for interspecies communication. Recent studies have highlighted the connection between the phosphotransferase system (PTS) and AI-2 QS, with this link being associated with protein-protein interaction (PPI) between HPr and LsrK. Here, we first discovered several AI-2 QSIs targeting the LsrK/HPr PPI site through molecular dynamics (MD) simulation, virtual screening, and bioassay evaluation. Of the 62 compounds purchased, eight compounds demonstrated significant inhibition in LsrK-based assays and AI-2 QS interference assays. Surface plasmon resonance (SPR) analysis confirmed that the hit compound 4171-0375 specifically bound to the LsrK-N protein (HPr binding domain, KD = 2.51 × 10-5 M), and therefore the LsrK/HPr PPI site. The structure-activity relationships (SARs) emphasized the importance of hydrophobic interactions with the hydrophobic pocket and hydrogen bonds or salt bridges with key residues of LsrK for LsrK/HPr PPI inhibitors. These new AI-2 QSIs, especially 4171-0375, exhibited novel structures, significant LsrK inhibition, and were suitable for structural modification to search for more effective AI-2 QSIs.

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors.

The PB2 subunit of the influenza RNA-dependent RNA polymerase (RdRp) has been identified as a promising target for the treatment of influenza. To expand the chemical space of the known influenza polymerase PB2 inhibitor-pimodivir (formerly VX-787) and improve its pharmacokinetic profile, two pimodivir analogs containing 2,3-dihydro-imidazopyridine fragment (comp. I and comp. II) were designed, synthesized, and evaluated for anti-influenza virus activity. In the cytopathic effect (CPE) inhibition assay, comp. I and comp. II showed IC50 values of 0.07 and 0.09 µM for A/Puerto Rico/8/34 (H1N1) and 0.04 and 0.07 µM for A/Hong Kong/8/68 (H3N2), respectively. Protein-binding affinity assay results showed a concentration-dependent association and dissociation pattern, with KD values of 1.398 and 1.670 µM, respectively. In vitro metabolic stability assays showed that comp. I and comp. II exhibited good stability to liver microsomes and considerably less sensitivity to aldehyde oxidase compared to pimodivir. The binding modes of comp. I and comp. II were similar to those of VX-787; however, comp. I and comp. II had lower structural adaptability to PB2 than VX-787. Our results provide helpful information regarding the structure-activity relationship for the design of novel PB2 inhibitors and a reference for the development of drugs containing 2,3-dihydro-imidazopyridine fragments.

Identifying Dopamine D3 Receptor Ligands through Virtual Screening and Exploring the Binding Modes of Hit Compounds.

The dopamine D3 receptor (D3R) is an important central nervous system target for treating various neurological diseases. D3R antagonists modulate the improvement of psychostimulant addiction and relapse, while D3R agonists can enhance the response to dopaminergic stimulation and have potential applications in treating Parkinson's disease, which highlights the importance of identifying novel D3R ligands. Therefore, we performed auto dock Vina-based virtual screening and D3R-binding-affinity assays to identify human D3R ligands with diverse structures. All molecules in the ChemDiv library (>1,500,000) were narrowed down to a final set of 37 molecules for the binding assays. Twenty-seven compounds exhibited over 50% inhibition of D3R at a concentration of 10 µM, and 23 compounds exhibited over 70% D3R inhibition at a concentration of 10 µM. Thirteen compounds exhibited over 80% inhibition of D3R at a concentration of 10 µM and the IC50 values were measured. The IC50 values of the five compounds with the highest D3R-inhibition rates ranged from 0.97 µM to 1.49 µM. These hit compounds exhibited good structural diversity, which prompted us to investigate their D3R-binding modes. After trial and error, we combined unbiased molecular dynamics simulation (MD) and molecular mechanics generalized Born surface area (MM/GBSA) binding free-energy calculations with the reported protein−ligand-binding pose prediction method using induced-fit docking (IFD) and binding pose metadynamics (BPMD) simulations into a self-consistent and computationally efficient method for predicting and verifying the binding poses of the hit ligands to D3R. Using this IFD-BPMD-MD-MM/GBSA method, we obtained more accurate and reliable D3R−ligand-binding poses than were obtained using the reported IFD-BPMD method. This IFD-BPMD-MD-MM/GBSA method provides a novel paradigm and reference for predicting and validating other protein−ligand binding poses.

Assessing the effects of short-term traffic restriction policies on traffic-related air pollutants.

The implementation of short-term traffic restriction policies (TRPs) during major events positively influences the traffic emission reduction. However, few studies explore the impact of diesel vehicle emissions on air quality during short-term TRP. In particular, the intertwined influences of short-term TRP and Spring Festival remains unclear. Based on Beijing 2022 Olympic Games, this study analyzed the spatiotemporal changes in urban air quality and diesel vehicle emission during short-term TRP. The results showed that the TRPs and Spring Festival contributed equally to the improvement of air quality and reduction of diesel vehicle emissions. The "interruption-recovery" pattern of short-term TRPs is characterized by a longer duration and a slower decline/recovery rate. Additionally, the individual contribution rate of diesel vehicle emissions to urban air pollutants was 15-20 % higher than that of meteorological factors during short-term TRPs.

Correlations Between Mandible Condylar Structures and External Ear Deformities in Hemifacial Microsomia With Three-Dimensional Analysis.

ABSTRACT: This study aimed to explore correlations between mandible and ear deformities and quantitative volumetric relations between condylar structures and external ear in hemifacial microsomia. The authors reconstructed three-dimensional craniofacial models from 212 patients with unilateral hemifacial microsomia (the unaffected side as the controls). Patients were evaluated by Pruzansky-Kaban and Marx classification, and divided into 3 age groups (0-6, 7-12, and >12 years of age). The mandible condylar structures, including condyle and the condylar skeletal unit, were selected (except the classification of the mandibular or ear deformities (M3)). Along with the external ear (except the classification of the mandibular or ear deformities (E4)), their volumes were measured and analyzed. Spearman correlation coefficient analysis was applied. There was a positive correlation between the mandible and ear deformities (r = 0.301, P   <  0.001). Either between the condyle and external ear ( P  = 0.071-0.493) or between the condylar unit and external ear ( P  = 0.080 - 0.488), there were no volumetric relations on the affected side, whereas on the unaffected side were (r = 0.492-0.929 for condyle, r = 0.443-0.929 for the condylar unit, P  < 0.05). In most cases, the condylar structures of the classification of the mandibular or ear deformities (M2b) were significantly smaller than the classification of the mandibular or ear deformities (M2a). Results suggested deformities of mandibular condylar structures and ear did not correlate, although deformities of mandible and ear did. The condylar deformity might develop independently from microtia and be more severe within relatively more abnormal temporomandibular joints.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs.

BACKGROUND: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide's in vivo antiviral activities are mainly attributed to its metabolite-tizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first-pass effects in the liver. It was thought that this might be due to the unstable acyloxy bond of nitazoxanide. OBJECTIVE: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. METHOD: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. RESULTS: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by the equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. CONCLUSION: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors.

Influenza A virus is the main cause of worldwide epidemics and annual influenza outbreaks in humans. In this study, a virtual screen was performed to identify compounds that interact with the PB2 cap-binding domain (CBD) of influenza A polymerase. A virtual screening workflow based on Glide docking was used to screen an internal database containing 8417 molecules, and then the output compounds were selected based on solubility, absorbance, and structural fingerprints. Of the 16 compounds selected for biological evaluation, six compounds were identified that rescued cells from H1N1 virus-mediated death at non-cytotoxic concentrations, with EC50 values ranging from 2.5-55.43 µM, and that could bind to the PB2 CBD of H1N1, with Kd values ranging from 0.081-1.53 µM. Molecular dynamics (MD) simulations of the docking complexes of our active compounds revealed that each compound had its own binding characteristics that differed from those of VX-787. Our active compounds have novel structures and unique binding modes with PB2 proteins, and are suitable to serve as lead compounds for the development of PB2 inhibitors. An analysis of the MD simulation also helped us to identify the dominant amino acid residues that play a key role in binding the ligand to PB2, suggesting that we should focus on increasing and enhancing the interaction between inhibitors and these major amino acids during lead compound optimization to obtain more active PB2 inhibitors.

Identification of novel influenza polymerase PB2 inhibitors using virtual screening approach and molecular dynamics simulation analysis of active compounds.

Hierarchical virtual screening combined with ADME prediction and cluster analysis methods were used to identify influenza virus PB2 inhibitors with high activity, good druggability properties, and diverse structures. The 200,000 molecules in the ChemDiv core library were narrowed down to a final set of 97 molecules, of which six compounds were found to rescue cells from both H1N1 and H3N2 virus-induced CPE with EC50 values ranging from 5.81 µM to 42.77 µM, and could bind to the PB2 CBD of H1N1, with Kd values of 0.11 µM to 6.4 µM. The six compounds have novel structures and low molecular weight and are, thus, suitable serve as lead compounds for development as PB2 inhibitors. A receptor-based pharmacophore model was successfully constructed using key amino acid residues for the binding of inhibitors to PB2, provided by the MD simulations. This pharmacophore model suggested that to improve the activity of our active compounds, we should mainly focus on optimizing their existing structures with the aim of increasing their adaptability to the binding site, rather than adding chemical fragments to increase their binding to adjacent sites. This pharmacophore construction method facilitates the creation of a reasonable pharmacophore model without the need to fully understand the structure-activity relationships, and our descriptions provide a useful reference for similar research.

Ilomastat contributes to the survival of mouse after irradiation via promoting the recovery of hematopoietic system.

Ilomastat, a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), has drawn attentions for its function in alleviating radiation damage. However, the detailed mechanisms of Ilomastat's protection from animal model remain not fully clear. In this study, the C57BL/6 mice were pre-administrated with Ilomastat or vihicle for 2 h, and then total body of mice were exposed to 6 Gy of γ-rays. The protective effect of Ilomastat on the hematopoietic system in the irradiated mice were investigated. We found that pretreatment with Ilomastat significantly reduced the level of TGF-ß1 and TNF-α, and elevated the number of bone marrow (BM) mononuclear cells in the irradiated mice. Ilomastat pretreatment also increased the fraction of BM hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) at day 30 after irradiation, and protected the spleen of mouse from irradiation. These results suggest that Ilomastat promotes the recovery of hematopoietic injury in the irradiated mice, and thus contributes to the survival of mouse after irradiation.

Identification of Novel Influenza Polymerase PB2 Inhibitors Using a Cascade Docking Virtual Screening Approach.

To discover novel inhibitors that target the influenza polymerase basic protein 2 (PB2) cap-binding domain (CBD), commercial ChemBridge compound libraries containing 384,796 compounds were screened using a cascade docking of LibDock-LigandFit-GOLD, and 60 compounds were selected for testing with cytopathic effect (CPE) inhibition assays and surface plasmon resonance (SPR) assay. Ten compounds were identified to rescue cells from H1N1 virus-mediated death at non-cytotoxic concentrations with EC50 values ranging from 0.30 to 67.65 µM and could bind to the PB2 CBD of H1N1 with Kd values ranging from 0.21 to 6.77 µM. Among these, four compounds (11D4, 12C5, 21A5, and 21B1) showed inhibition of a broad spectrum of influenza virus strains, including oseltamivir-resistant ones, the PR/8-R292K mutant (H1N1, recombinant oseltamivir-resistant strain), the PR/8-I38T mutant (H1N1, recombinant baloxavir-resistant strain), and the influenza B/Lee/40 virus strain. These compounds have novel chemical scaffolds and relatively small molecular weights and are suitable for optimization as lead compounds. Based on sequence and structure comparisons of PB2 CBDs of various influenza virus subtypes, we propose that the Phe323/Gln325, Asn429/Ser431, and Arg355/Gly357 mutations, particularly the Arg355/Gly357 mutation, have a marked impact on the selectivities of PB2 CBD-targeted inhibitors of influenza A and influenza B.

PROTACs: New method to degrade transcription regulating proteins.

Transcription is the fundamental process in all living organisms. A variety of important proteins, such as NRs, BETs, HDACs and many others are involved in transcription process. In general, overexpression of these proteins would cause many diseases. Some approved therapeutics employed inhibitors to regulate the transcription process, however, the results are far from satisfying. Therefore, it is in high demand to develop new technology to improve the therapeutic effects. In recent years, proteolysis-targeting chimaera (PROTAC) turned out to be a novel efficient therapeutic method to treat various diseases which were caused by proteins overexpression. PROTAC molecules are bifunctional small molecules that simultaneously bind a target protein and an E3-ubiquitin ligase, thus causing ubiquitination and subsequent degradation of the target protein by the proteasome. In contrast to traditional inhibitors, PROTACs showed higher efficiency to tackle the diseases which were caused by protein overexpression due to their excellent performance for degrading target proteins in transcription regulation. In this review, 29 kinds of PROTACs targeting transcription regulator proteins are summarized, and meanwhile the advantages of PROTACs are highlighted. Furthermore, several examples of PROTACs regulating the transcription for the treatment of diseases and functioning as tools for biological research are also disscussed.

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.

SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

Development of Novel Anti-influenza Thiazolides with Relatively Broad-Spectrum Antiviral Potentials.

Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug resistance to specific anti-influenza virus drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug, nitazoxanide, with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza virus potentials, with 10-fold improvement compared to results with nitazoxanide, and were effective against a variety of influenza virus subtypes including oseltamivir-resistant strains. Notably, the combination using compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effects against oseltamivir-resistant strains. Mode-of-action analysis demonstrated that compounds 4a/4d acted at the late phase of the viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of upregulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, the results of our study indicated the direction to optimize nitazoxanide as an anti-influenza drug and discovered two candidates with novel structures, compounds 4a/4d, that have relatively broad-spectrum antiviral potentials.

Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication.

Ricin is a highly toxic type 2 ribosome-inactivating protein (RIP) which is extracted from the seeds of castor beans. Ricin is considered a potential bioterror agent and no effective antidote for ricin exists so far. In this study, by structural modification of a retrograde transport blocker Retro-2cycl, a series of novel compounds were obtained. The primary screen revealed that compound 27 has an improved anti-ricin activity compare to positive control. In vitro pre-exposure evaluation in Madin-Darby Canine Kidney (MDCK) cells demonstrated that 27 is a powerful anti-ricin compound with an EC50 of 41.05 nmol/L against one LC (lethal concentration, 5.56 ng/mL) of ricin. Further studies surprisingly indicated that 27 confers post-exposure activity against ricin intoxication. An in vivo study showed that 1 h post-exposure administration of 27 can improve the survival rate as well as delay the death of ricin-intoxicated mice. A drug combination of 27 with monoclonal antibody mAb4C13 rescued mice from one LD (lethal dose) ricin challenge and the survival rate of tested animals is 100%. These results represent, for the first time, indication that small molecule retrograde transport blocker confers both in vitro and in vivo post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.

Structure based discovery of novel hexokinase 2 inhibitors.

Hexokinase 2 (HK2) is over-expressed in most of human cancers and has been proved to be a promising target for cancer therapy. In this study, based on the structure of HK2, we screened over 6 millions of compounds to obtain the lead. A total of 26 (E)-N'-(2,3,4-trihydroxybenzylidene) arylhydrazide derivatives were then designed, synthesized, and evaluated for their HK2 enzyme activity and IC50 values against two cancer cell lines. Most of the 26 target compounds showed excellently in vitro activity. Among them, compound 3j showed the strongest inhibitory effects on HK2 enzyme activity with an IC50 of 0.53 ± 0.13 µM and exhibited the most potent growth inhibition against SW480 cells with an IC50 of 7.13 ± 1.12 µM, which deserves further studies.

Synthesis of New Lathyrane Diterpenoid Derivatives from Euphorbia lathyris and Evaluation of Their Anti-Inflammatory Activities.

Euphorbia factor L3 , a lathyrane diterpenoid extracted from Euphorbia lathyris, was found to display good anti-inflammatory activity with very low cytotoxicity. To find more potent anti-inflammatory drugs, two series of Euphorbia factor L3 derivatives with fatty and aromatic acids were designed and synthesized. Among them, lathyrane derivative 5n exhibited most potent inhibition on LPS-induced NO production in RAW264.7 cells with no obvious cytotoxicity. To determine the key characteristics of Euphorbia factor L3 derivatives that contribute to anti-inflammatory activity, we conducted a structure-activity relationship study of these compounds.