Front Pharmacol. 2022 Aug 15;13:901340. doi: 10.3389/fphar.2022.901340. eCollection 2022.

ABSTRACT

Background: Sodium-glucose cotransporter 2 (SGLT2), also known as solute carrier family 5 member 2 (SLC5A2), is a promising target for a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Increasing evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart and other tissues. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with their binding force, location of targets in the SGLT2 networks, targets involvement in signaling pathways, and their tissue-specific expression. Methods: Thus, to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and metformin and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms ( autophagy, oxidative stress, aging, senescence, inflammation, AMPK pathways, and mTOR pathways) which seem to be crucial to elucidating the SGLT2 role in a variety of clinical manifestations. Results: Analysis of SGLT2 and its network components' expression confidence identified selected organs in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery according to the TISSUES database. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. The shortest path analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were not only ADIPOQ, INS, GLUT4, ACE, and GLUT1 but also less recognized ILK and ADCY7. Among other interactors which appeared in multiple shortest-path analyses were GPT, COG2, and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM-related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1), cancer-related terms, neuroactive ligand-receptor interaction, and neutrophil-mediated immunity. Conclusion: This study provides comprehensive and ranked information about the SGLT2 interaction network in the context of tissue expression and can help to predict the clinical effects of the SGLT2i.

PMID:36046822 | PMC:PMC9421436 | DOI:10.3389/fphar.2022.901340

Mol Pharm. 2022 Aug 31. doi: 10.1021/acs.molpharmaceut.2c00255. Online ahead of print.

ABSTRACT

Riluzole (RLZ) is a neuroprotective drug indicated for amyotrophic lateral sclerosis. To examine the feasibility of RLZ for repositioning as an anti-inflammatory bowel disease (IBD) drug, RLZ (2, 5, and 10 mg/kg) was administered orally to rats with colitis induced by 2,4-dinitrobenzenesulfonic acid. Oral RLZ was effective against rat colitis in a dose-dependent manner, which was statistically significant at doses over 5 mg/kg. To address safety issues upon repositioning and further improve anti-colitic effectiveness, RLZ was coupled with salicylic acid (SA) via an azo-bond to yield RLZ-azo-SA (RAS) for the targeted colonic delivery of RLZ. Upon oral gavage, RAS (oral RAS) was efficiently delivered to and activated to RLZ in the large intestine, and systemic absorption of RLZ was substantially reduced. Oral RAS ameliorated colonic damage and inflammation in rat colitis and was more effective than oral RLZ and sulfasalazine, a current anti-IBD drug. Moreover, oral RAS potently inhibited glycogen synthase kinase 3β (GSK3β) in the inflamed distal colon, leading to the suppression of NFκB activity and an increase in the level of the anti-inflammatory cytokine interleukin-10. Taken together, RAS, which enables RLZ to be delivered to and inhibit GSK3β in the inflamed colon, may facilitate repositioning of RLZ as an anti-IBD drug.

PMID:36043999 | DOI:10.1021/acs.molpharmaceut.2c00255

Genes Genomics. 2022 Aug 30. doi: 10.1007/s13258-022-01308-y. Online ahead of print.

ABSTRACT

BACKGROUND: The innate immune regulation, especially by the type I IFN signature in the CD14+ monocytes, is known to be critical in the pathogenesis of autoimmune Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE).

OBJECTIVE: Since patients with one condition can be overlapped with another, this study is to identify shared differentially expressed genes (DEGs) in SjS and SLE compared to healthy controls (HCs) and refine transcriptomic profiles with the integrated Reactome and gene-drug network analysis for an anti-inflammation therapy.

METHODS: CD14+ monocytes were purified from whole blood of SjS and SLE patients (females, ages from 32 to 62) and subject to bulk RNA-sequencing, followed by data analyses for comparison with HC monocytes (females, ages 30 and 33). Functional categorizations, using Gene Ontology (GO) and the Reactome pathway analysis, were performed and DEGs associated with therapeutic drugs were identified from the Drug Repurposing Hub (DHUB) database.

RESULTS: The GO analysis revealed that DEGs in the inflammatory response and the cellular response to cytokine were highly enriched in both conditions. A propensity toward M1 macrophage differentiation appears to be prominent in SjS while the Response to Virus was significant in SLE monocytes. Through the Reactome pathway analysis, DEGs in the IFN signaling and the cytokine signaling in immune system were most significantly enriched in both. Upregulation of NGF-induced transcription activity in SjS and the complement cascade activity in SLE were also noted. Multiple anti-inflammatory drugs, such as prostaglandin-endoperoxide synthase and angiotensin-I-converting- enzyme were associated with the DEGs in these conditions.

CONCLUSIONS: Taken together, our analysis indicates distinct inflammatory transcriptomic profiles shared in SjS and SLE monocytes. Comprehensive characterizations of the data from these conditions will ultimately allow differential diagnosis of each condition and identification of therapeutic targets.

PMID:36040684 | DOI:10.1007/s13258-022-01308-y

Antimicrob Agents Chemother. 2022 Aug 30:e0076222. doi: 10.1128/aac.00762-22. Online ahead of print.

ABSTRACT

Accumulating evidence suggests that drug repurposing has drawn attention as an anticipative strategy for controlling tuberculosis (TB), considering the dwindling drug discovery and development pipeline. In this study, we explored the antigout drug febuxostat and evaluated its antibacterial activity against Mycobacterium species. Based on MIC evaluation, we found that febuxostat treatment significantly inhibited mycobacterial growth, especially that of Mycobacterium tuberculosis (Mtb) and its phylogenetically close neighbors, M. bovis, M. kansasii, and M. shinjukuense, but these microorganisms were not affected by allopurinol and topiroxostat, which belong to a similar category of antigout drugs. Febuxostat concentration-dependently affected Mtb and durably mediated inhibitory functions (duration, 10 weeks maximum), as evidenced by resazurin microtiter assay, time-kill curve analysis, phenotypic susceptibility test, and the Bactec MGIT 960 system. Based on these results, we determined whether the drug shows antimycobacterial activity against Mtb inside murine bone marrow-derived macrophages (BMDMs). Notably, febuxostat markedly suppressed the intracellular growth of Mtb in a dose-dependent manner without affecting the viability of BMDMs. Moreover, orally administered febuxostat was efficacious in a murine model of TB with reduced bacterial loads in both the lung and spleen without the exacerbation of lung inflammation, which highlights the drug potency. Taken together, unexpectedly, our data demonstrated that febuxostat has the potential for treating TB.

PMID:36040172 | DOI:10.1128/aac.00762-22

J Biol Chem. 2022 Aug 26:102417. doi: 10.1016/j.jbc.2022.102417. Online ahead of print.

ABSTRACT

Gamma crystallins play a major role in age-related lens transparency. Their destabilization by mutations and physical chemical insults is strongly associated with cataract formation. Therefore, drugs that increase their stability should have anti-cataract properties. To this end, here we screened 2,560 FDA-approved drugs and natural compounds for their ability to suppress or worsen H2 O2 and/or heat-mediated aggregation of bovine γ-crystallins. The top two drugs, Closantel (C), an anti-helmintic drug, and Gambogic Acid (G), a xanthonoid, attenuated thermal-induced protein unfolding as determined by fluorescence spectroscopy, aggregation as shown by turbidimetry, dynamic light scattering, and electron microscopy of human or mouse recombinant crystallins. Furthermore, binding studies using fluorescence inhibition and hydrophobic pocket-binding molecule bis-ANS revealed static binding of C and G to hydrophobic sites with medium-to-low affinity. Molecular docking to HγD and other γ-crystallins also revealed two binding sites, one in the "NC-pocket" (residues 50-150) of HγD, and one spanning the "NC-tail" (residues 56-61 to 168-174 in the C-terminal domain). Notably, several of these binding sites overlap with those of the protective mini αA-crystallin chaperone peptide, MAC. Mechanistic studies using Bis-ANS as a proxy drug showed it bound to MAC sites, improved Tm of both H2O2 oxidized and native HyD, and suppressed turbidity of oxidized HγD, most likely by trapping exposed hydrophobic sites. The extent to which these drugs act as α-crystallin mimetics and reduce cataract progression remains to be demonstrated. This study provides initial insights into binding properties of C and G to γ-crystallins.

PMID:36037967 | DOI:10.1016/j.jbc.2022.102417

STAR Protoc. 2022 Aug 4;3(3):101641. doi: 10.1016/j.xpro.2022.101641. eCollection 2022 Sep 16.

ABSTRACT

Drug repositioning represents a cost- and time-efficient strategy for drug development. Here, we present a workflow of in silico screening of ACE2 enzymatic activators to treat COVID-19-induced metabolic complications. By using structure-based virtual screening and signature-based off-target effect identification via the Connectivity Map database, we provide a ranked list of the repositioning candidates as potential ACE2 enzymatic activators to ameliorate COVID-19-induced metabolic complications. The workflow can also be applied to other diseases with ACE2 as a potential target. For complete details on the use and execution of this protocol, please refer to Li et al. (2022).

PMID:36035796 | PMC:PMC9350712 | DOI:10.1016/j.xpro.2022.101641

Front Pharmacol. 2022 Aug 11;13:958196. doi: 10.3389/fphar.2022.958196. eCollection 2022.

ABSTRACT

Myotonia congenita (MC) is an inherited rare disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. It is caused by loss-of-function mutations in the skeletal muscle chloride channel ClC-1, important for the stabilization of resting membrane potential and for the repolarization phase of action potentials. Thanks to in vitro functional studies, the molecular mechanisms by which ClC-1 mutations alter chloride ion influx into the cell have been in part clarified, classifying them in "gating-defective" or "expression-defective" mutations. To date, the treatment of MC is only palliative because no direct ClC-1 activator is available. An ideal drug should be one which is able to correct biophysical defects of ClC-1 in the case of gating-defective mutations or a drug capable to recover ClC-1 protein expression on the plasma membrane for trafficking-defective ones. In this study, we tested the ability of niflumic acid (NFA), a commercial nonsteroidal anti-inflammatory drug, to act as a pharmacological chaperone on trafficking-defective MC mutants (A531V, V947E). Wild-type (WT) or MC mutant ClC-1 channels were expressed in HEK293 cells and whole-cell chloride currents were recorded with the patch-clamp technique before and after NFA incubation. Membrane biotinylation assays and western blot were performed to support electrophysiological results. A531V and V947E mutations caused a decrease in chloride current density due to a reduction of ClC-1 total protein level and channel expression on the plasma membrane. The treatment of A531V and V947E-transfected cells with 50 µM NFA restored chloride currents, reaching levels similar to those of WT. Furthermore, no significant difference was observed in voltage dependence, suggesting that NFA increased protein membrane expression without altering the function of ClC-1. Indeed, biochemical experiments confirmed that V947E total protein expression and its plasma membrane distribution were recovered after NFA incubation, reaching protein levels similar to WT. Thus, the use of NFA as a pharmacological chaperone in trafficking defective ClC-1 channel mutations could represent a good strategy in the treatment of MC. Because of the favorable safety profile of this drug, our study may easily open the way for confirmatory human pilot studies aimed at verifying the antimyotonic activity of NFA in selected patients carrying specific ClC-1 channel mutations.

PMID:36034862 | PMC:PMC9403836 | DOI:10.3389/fphar.2022.958196

iScience. 2022 Aug 2;25(9):104862. doi: 10.1016/j.isci.2022.104862. eCollection 2022 Sep 16.

ABSTRACT

Increasing antibiotic resistance among ocular pathogens often results in treatment failure for blinding infections such as endophthalmitis. Hence, newer therapeutics is needed to combat multidrug-resistant infections. Here, we show a drug repurposing approach using a connectivity map based on temporal transcriptomics of Staphylococcus aureus (SA) infected mouse retina. The analysis predicted three non-antibiotic drugs, Dequalinium chloride (DC), Clofilium tosylate (CT), and Glybenclamide (Glb) which reversed the SA infection signatures. Predicted drugs exhibited anti-inflammatory properties in human retinal cells against sensitive and resistant strains of SA. Intravitreal administration of all drugs reduced intraocular inflammation in SA-infected mouse eyes while DC and CT also reduced bacterial burden. Drug treatment improved visual function coinciding with reduced Caspase-3 mediated retinal cell death. Importantly, all drugs exhibited synergy with vancomycin in improving disease outcomes. Overall, our study identified three non-antibiotic drugs and demonstrated their therapeutic and prophylactic efficacies in ameliorating intraocular bacterial infection.

PMID:36034221 | PMC:PMC9399287 | DOI:10.1016/j.isci.2022.104862

Heliyon. 2022 Aug 11;8(8):e10108. doi: 10.1016/j.heliyon.2022.e10108. eCollection 2022 Aug.

ABSTRACT

Obesity is one of the most common global health problems for all age groups with obese people at risk of a variety of associated health complications. Consequently, there is a need to develop new therapies that lower body fat without the side effects. However, obesity is a complex and systemic disease, so that in vitro results are not easily translatable to clinical situations. A promising way to circumnavigate these issues is to reposition already approved drugs for new treatments, enabling a more streamlined drug discovery process due to the availability of pre-existing pharmacological and toxicological datasets. Chemical libraries, such as the Prestwick Chemical Library of 1200 FDA approved drugs, are available for this purpose. We have developed a simple semi-automated whole-organism approach to screening the Prestwick Chemical Library for those compounds which reduce fat content using the model organism Caenorhabditis elegans. Our whole-organism approach to high-throughput screening identified 9 "lead" compounds that reduced fat within 2 weeks in the model. Further screening and analysis provided 4 "hit" compounds (Midodrine, Vinpocetine, Fenoprofen and Lamivudine) that showed significant promise as drugs to reduce fat levels. The effects of these candidates were found to further reduce fat content in nematodes where an nhr-49/PPAR mutation resulted in "overweight" worms. Upon unblinding the "hit" compounds, they were found to have recently been shown to have anti-obesity effects in mammalian models too. In developing a whole-animal chemical screen to identify pharmacological agents as potential anti-obesity compounds, we demonstrate how chemical libraries can be rapidly and relatively cheaply profiled for active hits. Using the nematode Caenorhabditis elegans thus enables drugs to be assessed for applicability in humans and provides a new incentive to explore drug repurposing as a feasible and efficient way to identify new anti-obesity compounds.

PMID:36033279 | PMC:PMC9399480 | DOI:10.1016/j.heliyon.2022.e10108

Health Sci Rep. 2022 Aug 23;5(5):e798. doi: 10.1002/hsr2.798. eCollection 2022 Sep.

ABSTRACT

BACKGROUND AND AIMS: There is a sought for vaccines and antiviral agents as countermeasures for the recent monkeypox outbreak. Here, we aimed to review and discuss the repurposing potentials of smallpox vaccines and drugs in monkeypox outbreaks based on their comparative benefits and risks. Therefore, we conducted this rapid review and discussed the repurposing potentials of smallpox vaccines and drugs in monkeypox infection.

METHODS: Here, we searched Google Scholar and PubMed for relevant information and data. We found many articles that have suggested the use of smallpox vaccines and antiviral drugs in monkeypox outbreaks according to the study findings. We read the relevant articles to extract information.

RESULTS: According to the available documents, we found two replication-competent and one replication-deficient vaccinia vaccines were effective against Orthopoxvirus. However, the healthcare authorities have authorized second-generation live vaccina virus vaccines against Orthopoxvirus in many countries. Smallpox vaccine is almost 85% effective in preventing monkeypox infection as monkeypox virus, variola virus, and vaccinia virus are similar. The United States and Canada have approved a replication-deficient third-generation smallpox vaccine for the prevention of monkeypox infection. However, the widely used second-generation smallpox vaccines contain a live virus and replicate it into the human cell. Therefore, there is a chance to cause virus-induced complications among the vaccinated subjects. In those circumstances, the available Orthopoxvirus inhibitors might be a good choice for treating monkeypox infections as they showed similar efficacy in monkeypox infection in different animal model clinical trials. Also, the combined use of antiviral drugs and vaccinia immune globulin can enhance significant effectiveness in immunocompromised subjects.

CONCLUSION: Repurposing of these smallpox vaccines and antiviral agents might be weapons to fight monkeypox infection. Also, we recommend further investigations of smallpox vaccines and Orthopoxvirus inhibitors in a human model study to explore their exact role in human monkeypox infections.

PMID:36032515 | PMC:PMC9399446 | DOI:10.1002/hsr2.798

Sci Data. 2022 Aug 26;9(1):521. doi: 10.1038/s41597-022-01654-2.

ABSTRACT

Rare skin diseases include more than 800 diseases affecting more than 6.8 million patients worldwide. However, only 100 drugs have been developed for treating rare skin diseases in the past 38 years. To investigate potential treatments through drug repurposing for rare skin diseases, it is necessary to have a well-organized database to link all known disease causes, mechanisms, and related information to accelerate the process. Drug repurposing provides less expensive and faster potential options to develop treatments for known diseases. In this work, we designed and constructed a rare skin disease database (RSDB) as a disease-centered information depository to facilitate repurposing drug candidates for rare skin diseases. We collected and integrated associated genes, chemicals, and phenotypes into a network connected by pairwise relationships between different components for rare skin diseases. The RSDB covers 891 rare skin diseases defined by the Orphanet and GARD databases. The organized network for each rare skin disease comprises associated genes, phenotypes, and chemicals with the corresponding connections. The RSDB is available at https://rsdb.cmdm.tw .

PMID:36028515 | DOI:10.1038/s41597-022-01654-2

Future Med Chem. 2022 Aug 26. doi: 10.4155/fmc-2022-0074. Online ahead of print.

ABSTRACT

Background: We describe herein, an improved procedure for drug repurposing based on refined Medical Subject Headings (MeSH) terms and hierarchical clustering method. Materials & methods: In the present study, we have employed MeSH data from MEDLINE (2019), 1669 US FDA approved drugs from Open FDA and a refined set of MeSH terms. Refinement of MeSH terms was performed to include terms related to mechanistic information of drugs and diseases. Results and Conclusions: In-depth analysis of the results obtained, demonstrated greater efficiency of the proposed approach, based on refined MeSH terms and hierarchical clustering, in terms of number of selected drug candidates for repurposing. Further, analysis of misclustering and size of noise clusters suggest that the proposed approach is reliable and can be employed in drug repurposing.

PMID:36017692 | DOI:10.4155/fmc-2022-0074

Expert Rev Clin Pharmacol. 2022 Aug 26. doi: 10.1080/17512433.2022.2113388. Online ahead of print.

ABSTRACT

INTRODUCTION: Developing and evaluating novel compounds for treatment or prophylaxis of emerging infectious diseases is costly and time-consuming. Repurposing of already available marketed compounds is an appealing option as they already have an established safety profile. This approach could substantially reduce cost and time required to make effective treatments available to fight the COVID-19 pandemic. However, this approach is challenging since many drug candidates show efficacy in in vitro experiments, but fail to deliver effect when evaluated in clinical trials. Better approaches to evaluate in vitro data are needed, in order to prioritize drugs for repurposing.

AREAS COVERED: This article evaluates potential drugs that might be of interest for repurposing in the treatment of patients with COVID-19 disease. A pharmacometric simulation-based approach was developed to evaluate in vitro activity data in combination with expected clinical drug exposure, in order to evaluate the likelihood of achieving effective concentrations in patients.

EXPERT OPINION: The presented pharmacometric approach bridges in vitro activity data to clinically expected drug exposures, and could therefore be a useful compliment to other methods in order to prioritize repurposed drugs for evaluation in prospective randomized controlled clinical trials.

PMID:36017624 | DOI:10.1080/17512433.2022.2113388

Front Pharmacol. 2022 Aug 9;13:955648. doi: 10.3389/fphar.2022.955648. eCollection 2022.

ABSTRACT

COVID-19 caused by SARS-CoV-2 has raised a health crisis worldwide. The high morbidity and mortality associated with COVID-19 and the lack of effective drugs or vaccines for SARS-CoV-2 emphasize the urgent need for standard treatment and prophylaxis of COVID-19. The receptor-binding domain (RBD) of the glycosylated spike protein (S protein) is capable of binding to human angiotensin-converting enzyme 2 (hACE2) and initiating membrane fusion and virus entry. Hence, it is rational to inhibit the RBD activity of the S protein by blocking the RBD interaction with hACE2, which makes the glycosylated S protein a potential target for designing and developing antiviral agents. In this study, the molecular features of the S protein of SARS-CoV-2 are highlighted, such as the structures, functions, and interactions of the S protein and ACE2. Additionally, computational tools developed for the treatment of COVID-19 are provided, for example, algorithms, databases, and relevant programs. Finally, recent advances in the novel development of antivirals against the S protein are summarized, including screening of natural products, drug repurposing and rational design. This study is expected to provide novel insights for the efficient discovery of promising drug candidates against the S protein and contribute to the development of broad-spectrum anti-coronavirus drugs to fight against SARS-CoV-2.

PMID:36016554 | PMC:PMC9395726 | DOI:10.3389/fphar.2022.955648

Viruses. 2022 Aug 20;14(8):1827. doi: 10.3390/v14081827.

ABSTRACT

Dengue virus (DENV) is the causative agent of DENV infection. To tackle DENV infection, the development of therapeutic molecules as direct-acting antivirals (DAAs) has been demonstrated as a truly effective approach. Among various DENV drug targets, non-structural protein 5 (NS5)-a highly conserved protein among the family Flaviviridae-carries the RNA-dependent RNA polymerase (DENVRdRp) domain at the C-terminal, and its "N-pocket" allosteric site is widely considered for anti-DENV drug development. Therefore, in this study, we developed a pharmacophore model by utilising 41 known inhibitors of the DENVRdRp domain, and performed model screening against the FDA's approved drug database for drug repurposing against DENVRdRp. Herein, drugs complying with the pharmacophore hypothesis were further processed through standard-precision (SP) and extra-precision (XP) docking scores (DSs) and binding pose refinement based on MM/GBSA binding energy (BE) calculations. This resulted in the identification of four potential potent drugs: (i) desmopressin (DS: -10.52, BE: -69.77 kcal/mol), (ii) rutin (DS: -13.43, BE: -67.06 kcal/mol), (iii) lypressin (DS: -9.84, BE: -67.65 kcal/mol), and (iv) lanreotide (DS: -8.72, BE: -64.7 kcal/mol). The selected drugs exhibited relevant interactions with the allosteric N-pocket of DENVRdRp, including priming-loop and entry-point residues (i.e., R729, R737, K800, and E802). Furthermore, 100 ns explicit-solvent molecular dynamics simulations and end-point binding free energy assessments support the considerable stability and free energy of the selected drugs in the targeted allosteric pocket of DENVRdRp. Hence, these four drugs, repurposed as potent inhibitors of the allosteric site of DENVRdRp, are recommended for further validation using experimental assays.

PMID:36016449 | DOI:10.3390/v14081827

Viruses. 2022 Aug 11;14(8):1750. doi: 10.3390/v14081750.

ABSTRACT

Flavivirus infections, such as those caused by dengue and West Nile viruses, emerge as new challenges for the global healthcare sector. It has been found that these two viruses encode ion channels collectively termed viroporins. Therefore, drug molecules that block such ion-channel activity can serve as potential antiviral agents and may play a primary role in therapeutic purposes. We screened 2839 FDA-approved drugs and compounds in advanced experimental phases using three bacteria-based channel assays to identify such ion channel blockers. We primarily followed a negative genetic screen in which the channel is harmful to the bacteria due to excessive membrane permeabilization that can be relieved by a blocker. Subsequently, we cross-checked the outcome with a positive genetic screen and a pH-dependent assay. The following drugs exhibited potential blocker activities: plerixafor, streptomycin, tranexamic acid, CI-1040, glecaprevir, kasugamycin, and mesna were effective against dengue virus DP1. In contrast, idasanutlin, benzbromarone, 5-azacytidine, and plerixafor were effective against West Nile Virus MgM. These drugs can serve as future antiviral therapeutic agents following subsequent in vitro and in vivo efficacy studies.

PMID:36016372 | DOI:10.3390/v14081750

Vaccines (Basel). 2022 Aug 9;10(8):1284. doi: 10.3390/vaccines10081284.

ABSTRACT

Niclosamide, an FDA-approved oral anthelmintic drug, has broad biological activity including anticancer, antibacterial, and antiviral properties. Niclosamide has also been identified as a potent inhibitor of SARS-CoV-2 infection in vitro, generating interest in its use for the treatment or prevention of COVID-19. Unfortunately, there are several potential issues with using niclosamide for COVID-19, including low bioavailability, significant polypharmacology, high cellular toxicity, and unknown efficacy against emerging SARS-CoV-2 variants of concern. In this study, we used high-content imaging-based immunofluorescence assays in two different cell models to assess these limitations and evaluate the potential for using niclosamide as a COVID-19 antiviral. We show that despite promising preliminary reports, the antiviral efficacy of niclosamide overlaps with its cytotoxicity giving it a poor in vitro selectivity index for anti-SARS-CoV-2 inhibition. We also show that niclosamide has significantly variable potency against the different SARS-CoV-2 variants of concern and is most potent against variants with enhanced cell-to-cell spread including the B.1.1.7 (alpha) variant. Finally, we report the activity of 33 niclosamide analogs, several of which have reduced cytotoxicity and increased potency relative to niclosamide. A preliminary structure-activity relationship analysis reveals dependence on a protonophore for antiviral efficacy, which implicates nonspecific endolysosomal neutralization as a dominant mechanism of action. Further single-cell morphological profiling suggests niclosamide also inhibits viral entry and cell-to-cell spread by syncytia. Altogether, our results suggest that niclosamide is not an ideal candidate for the treatment of COVID-19, but that there is potential for developing improved analogs with higher clinical translational potential in the future.

PMID:36016172 | DOI:10.3390/vaccines10081284

Vaccines (Basel). 2022 Aug 3;10(8):1248. doi: 10.3390/vaccines10081248.

ABSTRACT

The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the situation is not under control because of the instability of RNA sequence patterns of SARS-CoV-2, which requires effective drugs. Several studies have suggested that the SARS-CoV-2 infection causing hub differentially expressed genes (Hub-DEGs). However, we observed that there was not any common hub gene (Hub-DEGs) in our analyses. Therefore, it may be difficult to take a common treatment plan against SARS-CoV-2 infections globally. The goal of this study was to examine if more representative Hub-DEGs from published studies by means of hub of Hub-DEGs (hHub-DEGs) and associated potential candidate drugs. In this study, we reviewed 41 articles on transcriptomic data analysis of SARS-CoV-2 and found 370 unique hub genes or studied genes in total. Then, we selected 14 more representative Hub-DEGs (AKT1, APP, CXCL8, EGFR, IL6, INS, JUN, MAPK1, STAT3, TNF, TP53, UBA52, UBC, VEGFA) as hHub-DEGs by their protein-protein interaction analysis. Their associated biological functional processes, transcriptional, and post-transcriptional regulatory factors. Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally.

PMID:36016137 | DOI:10.3390/vaccines10081248

Pharmaceutics. 2022 Aug 5;14(8):1634. doi: 10.3390/pharmaceutics14081634.

ABSTRACT

Toxoplasma gondii is a protozoan that infects up to a third of the world's population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when toxoplasmosis can cause miscarriage, or serious complications to the baby, or in an immunocompromised person, when the infection can possibly affect the patient's eyes or brain. To identify potential drug candidates that could counter toxoplasmosis, we selected 13 compounds which were pre-screened in silico based on the proteome of T. gondii to be evaluated in vitro against the parasite in a cell-based assay. Among the selected compounds, three demonstrated in vitro anti-T. gondii activity in the nanomolar range (almitrine, bortezomib, and fludarabine), and ten compounds demonstrated anti-T. gondii activity in the micromolar range (digitoxin, digoxin, doxorubicin, fusidic acid, levofloxacin, lomefloxacin, mycophenolic acid, ribavirin, trimethoprim, and valproic acid). Almitrine demonstrated a Selectivity Index (provided by the ratio between the Half Cytotoxic Concentration against human foreskin fibroblasts and the Half Effective Concentration against T. gondii tachyzoites) that was higher than 47, whilst being considered a lead compound against T. gondii. Almitrine showed interactions with the Na+/K+ ATPase transporter for Homo sapiens and Mus musculus, indicating a possible mechanism of action of this compound.

PMID:36015260 | DOI:10.3390/pharmaceutics14081634

Pharmaceutics. 2022 Jul 30;14(8):1590. doi: 10.3390/pharmaceutics14081590.

ABSTRACT

Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective anti-leishmanial through pointing to new drug targets in less time, having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future.

PMID:36015216 | DOI:10.3390/pharmaceutics14081590