ACS Infect Dis. 2022 Apr 11. doi: 10.1021/acsinfecdis.1c00629. Online ahead of print.

ABSTRACT

The global COVID-19 pandemic underscores the dire need for effective antivirals. Encouraging progress has been made in developing small-molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro). However, the development of papain-like protease (PLpro) inhibitors faces several obstacles. Nevertheless, PLpro represents a high-profile drug target given its multifaceted roles in viral replication. PLpro is involved in not only the cleavage of viral polyprotein but also the modulation of host immune response. In this study, we conducted a drug-repurposing screening of PLpro against the MedChemExpress bioactive compound library and identified three hits, EACC, KY-226, and tropifexor, as potent PLpro inhibitors with IC50 values ranging from 3.39 to 8.28 μM. The three hits showed dose-dependent binding to PLpro in the thermal shift assay. In addition, tropifexor inhibited the cellular PLpro activity in the FlipGFP assay with an IC50 of 10.6 μM. Gratifyingly, tropifexor showed antiviral activity against SARS-CoV-2 in Calu-3 cells at noncytotoxic concentrations. Overall, tropifexor represents a novel PLpro inhibitor that can be further developed as SARS-CoV-2 antivirals.

PMID:35404564 | DOI:10.1021/acsinfecdis.1c00629

Drug Deliv Transl Res. 2022 Apr 11. doi: 10.1007/s13346-022-01156-z. Online ahead of print.

ABSTRACT

Drug repurposing offers the chance to explore the full potential of existing drugs while reducing drug development time and costs. For instance, the anticonvulsant drug phenytoin (PHT) has been investigated for its wound healing properties. However, its poor solubility and variability of doses used topically limit its use. Hence, the aim of this study was to improve the properties and wound healing efficacy of PHT for the treatment of diabetic bedsores. PHT was encapsulated, using a modified ionic gelation method, in either positively or negatively charged chitosan-alginate nanoparticles (NPs), which possess previously demonstrated wound healing potential. These NPs were characterized by transmission electron microscopy, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. PHT-loaded NPs were evaluated in vivo for their pressure ulcers' healing potential using diabetic rats. The prepared NPs, especially the positively charged particles, exhibited superior wound healing efficacy compared to PHT suspension, with respect to healing rates, granulation tissue formation, tissue maturation, and collagen content. The positively charged NPs resulted in a 56.54% wound closure at day 7, compared to 37% for PHT suspension. Moreover, skin treated with these NPs showed a mature dermis structure with skin appendages, which were absent in all other groups, in addition to the highest collagen content of 63.65%. In conclusion, the use of a bioactive carrier enhanced the healing properties of PHT and allowed the use of relatively low doses of the drug. Our findings suggest that the prepared NPs offer an effective antibiotic-free delivery system for diabetic wound healing applications.

PMID:35403947 | DOI:10.1007/s13346-022-01156-z

Mol Ther Methods Clin Dev. 2022 Mar 17;25:147-157. doi: 10.1016/j.omtm.2022.03.005. eCollection 2022 Jun 9.

ABSTRACT

Research in the area of hallmarks of cancer has opened the possibility of designing new therapies based on modulating these cancer properties. We present here a screen designed to find chemicals that modulate epithelial-mesenchymal transitions (EMTs) in prostate cancer. For screening, we used a repurposing library and, as a readout, an FGFR2-based splicing reporter, which has been shown previously to be a sensor for EMTs. Various properties of cancer cells were assessed, signaling pathways investigated, and in vivo experiments in nude mice xenografts performed. The screen yielded three hit compounds (a T-type Ca channel inhibitor, an L-type Ca channel inhibitor, and an opioid antagonist) that switch FGFR2 splicing and induce an epithelial phenotype in prostate cancer cells. The compounds affected differently various properties of cancer cells, but all of them decreased cell migration, which is in line with modulating EMTs. We further present mechanistic insights into one of the compounds, nemadipine-A. The administration of nemadipine-A intraperitoneally in a nude mouse xenograft model of prostate cancer slowed tumor growth. To conclude, we show that knowledge of the molecular mechanisms that connect alternative splicing and various cancer properties may be used as a platform for drug development.

PMID:35402635 | PMC:PMC8971352 | DOI:10.1016/j.omtm.2022.03.005

Front Cardiovasc Med. 2022 Mar 24;9:842641. doi: 10.3389/fcvm.2022.842641. eCollection 2022.

ABSTRACT

Conventional drug screening methods search for a limited number of small molecules that directly interact with the target protein. This process can be slow, cumbersome and has driven the need for developing new drug screening approaches to counter rapidly emerging diseases such as COVID-19. We propose a pipeline for drug repurposing combining in silico drug candidate identification followed by in vitro characterization of these candidates. We first identified a gene target of interest, the entry receptor for the SARS-CoV-2 virus, angiotensin converting enzyme 2 (ACE2). Next, we employed a gene expression profile database, L1000-based Connectivity Map to query gene expression patterns in lung epithelial cells, which act as the primary site of SARS-CoV-2 infection. Using gene expression profiles from 5 different lung epithelial cell lines, we computationally identified 17 small molecules that were predicted to decrease ACE2 expression. We further performed a streamlined validation in the normal human epithelial cell line BEAS-2B to demonstrate that these compounds can indeed decrease ACE2 surface expression and to profile cell health and viability upon drug treatment. This proposed pipeline combining in silico drug compound identification and in vitro expression and viability characterization in relevant cell types can aid in the repurposing of FDA-approved drugs to combat rapidly emerging diseases.

PMID:35402570 | PMC:PMC8989014 | DOI:10.3389/fcvm.2022.842641

Front Genet. 2022 Mar 25;13:866474. doi: 10.3389/fgene.2022.866474. eCollection 2022.

ABSTRACT

Drug repositioning continues to be the most effective, practicable possibility to treat COVID-19 patients. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters target cells by binding to the ACE2 receptor via its spike (S) glycoprotein. We used molecular docking-based virtual screening approaches to categorize potential antagonists, halting ACE2-spike interactions by utilizing 450 FDA-approved chemical compounds. Three drug candidates (i.e., anidulafungin, lopinavir, and indinavir) were selected, which show high binding affinity toward the ACE2 receptor. The conformational stability of selected docked complexes was analyzed through molecular dynamics (MD) simulations. The MD simulation trajectories were assessed and monitored for ACE2 deviation, residue fluctuation, the radius of gyration, solvent accessible surface area, and free energy landscapes. The inhibitory activities of the selected compounds were eventually tested in-vitro using Vero and HEK-ACE2 cells. Interestingly, besides inhibiting SARS-CoV-2 S glycoprotein induced syncytia formation, anidulafungin and lopinavir also blocked S-pseudotyped particle entry into target cells. Altogether, anidulafungin and lopinavir are ranked the most effective among all the tested drugs against ACE2 receptor-S glycoprotein interaction. Based on these findings, we propose that anidulafungin is a novel potential drug targeting ACE2, which warrants further investigation for COVID-19 treatment.

PMID:35401674 | PMC:PMC8990323 | DOI:10.3389/fgene.2022.866474

Front Immunol. 2022 Mar 23;13:758440. doi: 10.3389/fimmu.2022.758440. eCollection 2022.

ABSTRACT

BACKGROUND: Endometriosis, classically viewed as a localized disease, is increasingly recognized as a systemic disease with multi-organ effects. This disease is highlighted by systemic inflammation in affected organs and by high comorbidity with immune-mediated diseases.

RESULTS: We provide genomic evidence to support the recognition of endometriosis as an inflammatory systemic disease. This was achieved through our genomics-led target prioritization, called 'END', that leverages the value of multi-layered genomic datasets (including genome-wide associations in disease, regulatory genomics, and protein interactome). Our prioritization recovered existing proof-of-concept therapeutic targeting in endometriosis and outperformed competing prioritization approaches (Open Targets and Naïve prioritization). Target genes at the leading prioritization revealed molecular hallmarks (and possibly the cellular basis as well) that are consistent with systemic disease manifestations. Pathway crosstalk-based attack analysis identified the critical gene AKT1. In the context of this gene, we further identified genes that are already targeted by licensed medications in other diseases, such as ESR1. Such analysis was supported by current interests targeting the PI3K/AKT/mTOR pathway in endometriosis and by the fact that therapeutic agents targeting ESR1 are now under active clinical trials in disease. The construction of cross-disease prioritization map enabled the identification of shared and distinct targets between endometriosis and immune-mediated diseases. Shared target genes identified opportunities for repurposing existing immunomodulators, particularly disease-modifying anti-rheumatic drugs (such as TNF, IL6 and IL6R blockades, and JAK inhibitors). Genes highly prioritized only in endometriosis revealed disease-specific therapeutic potentials of targeting neutrophil degranulation - the exocytosis that can facilitate metastasis-like spread to distant organs causing inflammatory-like microenvironments.

CONCLUSION: Improved target prioritization, along with an atlas of in silico predicted targets and repurposed drugs (available at https://23verse.github.io/end), provides genomic insights into endometriosis, reveals disease-specific therapeutic potentials, and expands the existing theories on the origin of disease.

PMID:35401535 | PMC:PMC8983833 | DOI:10.3389/fimmu.2022.758440

Front Aging Neurosci. 2022 Mar 18;14:752858. doi: 10.3389/fnagi.2022.752858. eCollection 2022.

ABSTRACT

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. To identify AD-related genes from transcriptomics and help to develop new drugs to treat AD. In this study, firstly, we obtained differentially expressed genes (DEG)-enriched coexpression networks between AD and normal samples in multiple transcriptomics datasets by weighted gene co-expression network analysis (WGCNA). Then, a convergent genomic approach (CFG) integrating multiple AD-related evidence was used to prioritize potential genes from DEG-enriched modules. Subsequently, we identified candidate genes in the potential genes list. Lastly, we combined deepDTnet and SAveRUNNER to predict interaction among candidate genes, drug and AD. Experiments on five datasets show that the CFG score of GJA1 is the highest among all potential driver genes of AD. Moreover, we found GJA1 interacts with AD from target-drugs-diseases network prediction. Therefore, candidate gene GJA1 is the most likely to be target of AD. In summary, identification of AD-related genes contributes to the understanding of AD pathophysiology and the development of new drugs.

PMID:35401145 | PMC:PMC8985410 | DOI:10.3389/fnagi.2022.752858

Eur J Med Chem. 2022 Mar 25;236:114318. doi: 10.1016/j.ejmech.2022.114318. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (P. aeruginosa) DK2 is a multidrug-resistant (MDR) gram-negative bacterial pathogen, being observed serious resistance to the 'last-resort' antibiotic, polymyxin B (PB). Combination therapies with adjuvants have emerged as effective strategies to reactivate the antibiotics resisted by MDR bacteria. Herein, we screened a library of approved drugs and found that niclosamide (NIC), an anthelmintic drug, could potentiate the efficacy of PB against MDR P. aeruginosa DK2. Next, a series of novel NIC-derived adjuvants were designed, synthesized, and evaluated the synergistic activity with PB. Among them, the combination of 15 with PB displayed superior elimination of P. aeruginosa DK2 in vitro and in vivo compared with the single administration. Moreover, this combination decelerated PB-resistance progress in DK2, along with lower potential toxicity. Overall, this study provides a strategy for development antibiotic adjuvants to potentiate PB against MDR P. aeruginosa infections.

PMID:35398731 | DOI:10.1016/j.ejmech.2022.114318

Drug Discov Today. 2022 Apr 5:S1359-6446(22)00132-5. doi: 10.1016/j.drudis.2022.04.001. Online ahead of print.

ABSTRACT

Drug repurposing is an appealing method to address the Coronavirus 2019 (COVID-19) pandemic because of their low cost and efficiency. We analyzed our in-house database of approved drug screens and compared their activity profiles with results from a severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) cytopathic effect (CPE) assay. The activity profiles of the human ether-à-go-go-related gene (hERG), phospholipidosis (PLD), and many cytotoxicity screens were significantly correlated with anti-SARS-CoV-2 activity. hERG inhibition is a nonspecific off-target effect that has contributed to promiscuous drug interactions, whereas drug-induced PLD is an undesirable effect linked to hERG blockers. Thus, this study identifies preferred drug candidates as well as chemical structures that should be avoided because of their potential to induce toxicity. Lastly, we highlight the hERG liability of anti-SARS-CoV-2 drugs currently enrolled in clinical trials. Teaser: Drug repurposing is an appealing method for the development of COVID-19 treatments; however, significant correlations observed between a SARS-CoV-2 cytopathic effect assay and hERG, phospholipidosis, and many cell viability assays raise concerns regarding the toxicity potentials of anti-SARS-CoV-2 drugs.

PMID:35395401 | DOI:10.1016/j.drudis.2022.04.001

Drug Discov Today. 2022 Apr 5:S1359-6446(22)00134-9. doi: 10.1016/j.drudis.2022.04.003. Online ahead of print.

ABSTRACT

Neurodegenerative diseases (NDs) are often age-related disorders that can cause dementia in people, usually over 65 years old, are still lacking effective therapies. Some NDs have recently been linked to toxic protein aggregates, for example Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington disease; therefore, mulating toxic protein aggregates would be a promising therapeutic strategy. Moreover, drug repurposing, in other words exploiting drugs that are already in use for another indication, has been attracting mounting attention for potential therapeutic purposes in NDs. Thus, in this review, we focus on summarizing a series of repurposed small-molecule drugs for eliminating or inhibiting toxic protein aggregates and further discuss their intricate molecular mechanisms to improve the current ND treatment. Taken together, these findings will shed new light on exploiting more repurposed small-molecule drugs targeting different types of toxic proteins to fight NDs in the future. Teaser: Drug repurposing has been gaining attention to yield therapeutic potential in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington disease.

PMID:35395400 | DOI:10.1016/j.drudis.2022.04.003

JAMA Netw Open. 2022 Apr 1;5(4):e226567. doi: 10.1001/jamanetworkopen.2022.6567.

ABSTRACT

IMPORTANCE: Cytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative based on multiomics phenotyping.

OBJECTIVE: To evaluate the association between treatment with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept and risk of incident ADRD.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted among US Medicare fee-for-service patients with rheumatoid arthritis aged 65 years and older from 2007 to 2017. Patients were categorized into 3 cohorts based on initiation of tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with a common comparator abatacept (a T-cell activation inhibitor). Analyses were conducted from August 2020 to August 2021.

MAIN OUTCOMES AND MEASURES: The main outcome was onset of ADRD based on diagnosis codes evaluated in 4 alternative analysis schemes: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazard regression after adjustment for 79 preexposure characteristics through propensity score matching.

RESULTS: After 1:1 propensity score matching to patients using abatacept, a total of 22 569 propensity score-matched patient pairs, including 4224 tofacitinib pairs (mean [SD] age 72.19 [5.65] years; 6945 [82.2%] women), 6369 tocilizumab pairs (mean [SD] age 72.01 [5.46] years; 10 105 [79.4%] women), and 11 976 TNF inhibitor pairs (mean [SD] age 72.67 [5.91] years; 19 710 [82.3%] women), were assessed. Incidence rates of ADRD varied from 2 to 18 per 1000 person-years across analyses schemes. There were no statistically significant associations of ADRD with tofacitinib (analysis 1: HR, 0.90 [95% CI, 0.55-1.51]; analysis 2: HR, 0.78 [95% CI, 0.53-1.13]; analysis 3: HR, 1.29 [95% CI, 0.72-2.33]; analysis 4: HR, 0.50 [95% CI, 0.21-1.20]), tocilizumab (analysis 1: HR, 0.82 [95% CI, 0.55-1.21]; analysis 2: HR, 1.05 [95% CI, 0.81-1.35]; analysis 3: HR, 1.21 [95% CI, 0.75-1.96]; analysis 4: HR, 0.78 [95% CI, 0.44-1.39]), or TNF inhibitors (analysis 1: HR, 0.93 [95% CI, 0.72-1.20]; analysis 2: HR, 1.02 [95% CI, 0.86-1.20]; analysis 3: HR, 1.13 [95% CI, 0.86-1.48]; analysis 4: 0.90 [95% CI, 0.60-1.37]) compared with abatacept. Results from prespecified subgroup analysis by age, sex, and baseline cardiovascular disease were consistent except in patients with cardiovascular disease, for whom there was a potentially lower risk of ADRD with TNF inhibitors vs abatacept, but only in analyses 2 and 4 (analysis 1: HR, 0.76 [95% CI, 0.50-1.16]; analysis 2: HR, 0.74 [95% CI, 0.56-0.99]; analysis 3: HR, 1.03 [95% CI, 0.65-1.61]; analysis 4: HR, 0.45 [95% CI, 0.21-0.98]).

CONCLUSIONS AND RELEVANCE: This cohort study did not find any association of risk of ADRD in patients treated with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept.

PMID:35394510 | DOI:10.1001/jamanetworkopen.2022.6567

J Comput Biol. 2022 Apr 7. doi: 10.1089/cmb.2021.0108. Online ahead of print.

ABSTRACT

This study formulates antiviral repositioning as a matrix completion problem wherein the antiviral drugs are along the rows and the viruses are along the columns. The input matrix is partially filled, with ones in positions where the antiviral drug has been known to be effective against a virus. The curated metadata for antivirals (chemical structure and pathways) and viruses (genomic structure and symptoms) are encoded into our matrix completion framework as graph Laplacian regularization. We then frame the resulting multiple graph regularized matrix completion (GRMC) problem as deep matrix factorization. This is solved by using a novel optimization method called HyPALM (Hybrid Proximal Alternating Linearized Minimization). Results of our curated RNA drug-virus association data set show that the proposed approach excels over state-of-the-art GRMC techniques. When applied to in silico prediction of antivirals for COVID-19, our approach returns antivirals that are either used for treating patients or are under trials for the same.

PMID:35394368 | DOI:10.1089/cmb.2021.0108

Eur Urol. 2022 Apr 4:S0302-2838(22)01678-5. doi: 10.1016/j.eururo.2022.03.009. Online ahead of print.

ABSTRACT

BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need.

OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC.

DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line.

RESULTS AND LIMITATIONS: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8).

CONCLUSIONS: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care.

PATIENT SUMMARY: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.

PMID:35393162 | DOI:10.1016/j.eururo.2022.03.009

Interdiscip Sci. 2022 Apr 7. doi: 10.1007/s12539-022-00511-5. Online ahead of print.

ABSTRACT

The identification of chemical-disease association types is helpful not only to discovery lead compounds and study drug repositioning, but also to treat disease and decipher pathomechanism. It is very urgent to develop computational method for identifying potential chemical-disease association types, since wet methods are usually expensive, laborious and time-consuming. In this study, molecular fingerprint, gene ontology and pathway are utilized to characterize chemicals and diseases. A novel predictor is proposed to recognize potential chemical-disease associations at the first layer, and further distinguish whether their relationships belong to biomarker or therapeutic relations at the second layer. The prediction performance of current method is assessed using the benchmark dataset based on ten-fold cross-validation. The practical prediction accuracies of the first layer and the second layer are 78.47% and 72.07%, respectively. The recognition ability for lead compounds, new drug indications, potential and true chemical-disease association pairs has also been investigated and confirmed by constructing a variety of datasets and performing a series of experiments. It is anticipated that the current method can be considered as a powerful high-throughput virtual screening tool for drug researches and developments.

PMID:35391615 | DOI:10.1007/s12539-022-00511-5

Drug Discov Today. 2022 Apr 4:S1359-6446(22)00131-3. doi: 10.1016/j.drudis.2022.03.021. Online ahead of print.

ABSTRACT

Clostridioides difficile bacteria can cause life-threatening diarrhea and colitis owing to limited treatment options and unacceptably high recurrence rates among infected patients. This necessitates the development of alternative routes for C. difficile treatment. Drug repurposing with new indications represents a proven shortcut. Here, we present a refined focus on 16 FDA-approved drugs that would be suitable for further development as potential anti-C.-difficile drugs. Of these drugs, clinical trials have been conducted on five currently used drugs; however, ursodeoxycholic acid is the only drug to enter Phase IV clinical trials to date. Thus, drug repurposing promotes the study of mechanistic and therapeutic strategies, providing new options for the development of next-generation anti-C.-difficile agents.

PMID:35390545 | DOI:10.1016/j.drudis.2022.03.021

Exp Parasitol. 2022 Apr 4:108250. doi: 10.1016/j.exppara.2022.108250. Online ahead of print.

ABSTRACT

Visceral leishmaniasis (VL) is the deadliest form of leishmaniasis without a safer treatment option. This study implies drug repurposing to find a novel antileishmanial compound, namely febrifugine dihydrochloride (FFG) targeting Leishmania antioxidant system. Starting with virtual screening revealed the high binding affinity and lead likeness of FFG against the trypanothione reductase (TR) enzyme of Leishmania donovani, followed by experimental validation. The promastigotes inhibition assay gave the IC50 concentration of FFG and Miltefosine (positive control) as 7.16 ± 1.39nM and 11.41 ± 0.29 μM, respectively. Their CC50 was found as 451 ± 12.73nM and 135.9 ± 5.94 μM, respectively. FFG has been shown to increase the reactive oxygen species (ROS), leading to apoptosis-like cell death among L. donovani promastigotes. Spleen touch biopsy resulted in 62% and 55% decreased parasite load with FFG and miltefosine treatment, respectively. Cytokine profiling has shown an increased proinflammatory cytokine response post-FFG treatment. Moreover, FFG is safe on the liver toxicity parameter in mice post-treatment.

PMID:35390313 | DOI:10.1016/j.exppara.2022.108250

J Biomol Struct Dyn. 2022 Apr 7:1-14. doi: 10.1080/07391102.2022.2059008. Online ahead of print.

ABSTRACT

SARS-CoV-2 Mpro is one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and is a crucial target for drug discovery. Unfortunately, there is not any potential drugs available to combat the action of SARS-CoV-2 Mpro. Based on the reports HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 Mpro, we have chosen few clinically trialed experimental and allophenylnorstatine (APNS) containing HIV-protease inhibitors (JE-2147, JE-533, KNI-227, KNI-272 & KNI-1931), to examine their binding affinities with SARS-CoV-2 Mpro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the binding mechanism of these five inhibitors to SARS-CoV-2 Mpro by merging molecular docking, molecular dynamics (MD) simulation and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (ΔGBind = -28.31 kcal/mol) due to an increased favorable van der Waals (ΔEvdw) interactions and decreased solvation (ΔGsolv) energies between the inhibitor and viral protease. JE-2147 shows a higher level of interactions as compared to JE-533 (-6.85 kcal/mol), KNI-227 (-18.36 kcal/mol), KNI-272 (-15.69 kcal/mol) and KNI-1931 (-21.59 kcal/mol) against SARS-CoV-2 Mpro. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Glu166, Pro168, Gln189, etc.) from the active site or near the active site regions with ≥1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 Mpro drugs.Communicated by Ramaswamy H. Sarma.

PMID:35388744 | DOI:10.1080/07391102.2022.2059008

J Int Med Res. 2022 Apr;50(4):3000605221090363. doi: 10.1177/03000605221090363.

ABSTRACT

OBJECTIVE: Hydroxychloroquine (HCQ) has been used during the coronavirus disease 2019 (COVID-19) pandemic because of its reported anti-viral activity. This study examined the association of chronic HCQ use with the incidence and complications of COVID-19.

METHODS: This retrospective cohort study included adults with rheumatoid arthritis and/or systemic lupus erythematosus who visited rheumatology clinics in three tertiary hospitals in Riyadh, Saudi Arabia between January 2019 and December 2020. Patients were categorized into two groups based on HCQ use. Data were obtained from the electronic health record and by interviews with patients. The primary study objective was the incidence of COVID-19 and its complications from March 2020 to February 2021.

RESULTS: Almost 11% of the study cohort was positive for COVID-19, and the incidence of COVID-19 was similar between HCQ users (11.11%) and nonusers (10.86%). Disease complication rates were similar in the study arms, and they mainly included fever, dry cough, fatigue, and breathing difficulty.

CONCLUSIONS: This study revealed no significant association between chronic HCQ use and the incidence of COVID-19, and disease complications were similar in the study arms.

PMID:35387504 | DOI:10.1177/03000605221090363

Front Pharmacol. 2022 Mar 21;13:854506. doi: 10.3389/fphar.2022.854506. eCollection 2022.

ABSTRACT

Statins, a class of lipid-lowering drugs, are used in drug repositioning for treatment of human cancer. However, the molecular mechanisms underlying statin-induced cancer cell death and autophagy are not clearly defined. In the present study, we showed that pitavastatin could increase apoptosis in a FOXO3a-dependent manner in the oral cancer cell line, SCC15, and the colon cancer cell line, SW480, along with the blockade of autophagy flux. The inhibition of autophagy by silencing the LC3B gene reduced apoptosis, while blockade of autophagy flux using its inhibitor, Bafilomycin A1, further induced apoptosis upon pitavastatin treatment, which suggested that autophagy flux blockage was the cause of apoptosis by pitavastatin. Further, the FOXO3a protein accumulated due to the blockade of autophagy flux which in turn was associated with the induction of ER stress by transcriptional upregulation of PERK-CHOP pathway, subsequently causing apoptosis due to pitavastatin treatment. Taken together, pitavastatin-mediated blockade of autophagy flux caused an accumulation of FOXO3a protein, thereby leading to the induction of PERK, ultimately causing CHOP-mediated apoptosis in cancer cells. Thus, the present study highlighted the additional molecular mechanism underlying the role of autophagy flux blockade in inducing ER stress, eventually leading to apoptosis by pitavastatin.

PMID:35387352 | PMC:PMC8977529 | DOI:10.3389/fphar.2022.854506

Front Pharmacol. 2022 Mar 21;13:879611. doi: 10.3389/fphar.2022.879611. eCollection 2022.

NO ABSTRACT

PMID:35387337 | PMC:PMC8978335 | DOI:10.3389/fphar.2022.879611