Pharmaceutics. 2021 Feb 25;13(3):302. doi: 10.3390/pharmaceutics13030302.

ABSTRACT

COVID-19 may lead to severe respiratory distress syndrome and high risk of death in some patients. So far (January 2021), only the antiviral remdesivir has been approved, although no significant benefits in terms of mortality and clinical improvement were recently reported. In a setting where effective and safe treatments for COVID-19 are urgently needed, drug repurposing may take advantage of the fact that the safety profile of an agent is already well known and allows rapid investigation of the efficacy of potential treatments, at lower costs and with reduced risk of failure. Furthermore, novel pharmaceutical formulations of older agents (e.g., aerosolized administration of chloroquine/hydroxychloroquine, remdesivir, heparin, pirfenidone) have been tested in order to increase pulmonary delivery and/or antiviral effects of potentially active drugs, thus overcoming pharmacokinetic issues. In our review, we will highlight the importance of the drug repurposing strategy in the context of COVID-19, including regulatory and ethical aspects, with a specific focus on novel pharmaceutical formulations and routes of administration.

PMID:33668969 | DOI:10.3390/pharmaceutics13030302

Molecules. 2021 Feb 13;26(4):986. doi: 10.3390/molecules26040986.

ABSTRACT

Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.

PMID:33668428 | DOI:10.3390/molecules26040986

Transl Oncol. 2021 Mar 2;14(5):101048. doi: 10.1016/j.tranon.2021.101048. Online ahead of print.

ABSTRACT

Pediatric MLL-rearranged acute myeloid leukemia (AML) has a generally unfavorable outcome, primarily due to relapse and drug resistance. To overcome these difficulties, new therapeutic agents are urgently needed. Yet, implementing novel drugs for clinical use is a time-consuming, laborious, costly and high-risk process. Therefore, we applied a drug-repositioning strategy by screening drug libraries, comprised of >4000 compounds that are mostly FDA-approved, in a high-throughput format on primary MLL-rearranged AML cells. Here we identified pyrvinium pamoate (pyrvinium) as a novel candidate drug effective against MLL-rearranged AML, eliminating all cell viability at <1000 nM. Additional screening of identified drug hits on non-leukemic bone marrow samples, resulted in a decrease in cell viability of ∼50% at 1000 nM pyrvinium, suggesting a therapeutic window for targeting leukemic cells specifically. Validation of pyrvinium on an extensive panel of AML cell lines and primary AML samples showed comparable viabilities as the drug screen data, with pyrvinium achieving IC50 values of <80 nM in these samples. Remarkably, pyrvinium also induced cell toxicity in primary MLL-AF10+ AML cells, an MLL-rearrangement associated with a poor outcome. While pyrvinium is able to inhibit the Wnt pathway in other diseases, this unlikely explains the efficacy we observed as β-catenin was not expressed in the AML cells tested. Rather, we show that pyrvinium co-localized with the mitochondrial stain in cells, and hence may act by inhibiting mitochondrial respiration. Overall, this study shows that pyrvinium is highly effective against MLL-rearranged AML in vitro, and therefore represents a novel potential candidate for further studies in MLL-rearranged AML.

PMID:33667892 | DOI:10.1016/j.tranon.2021.101048

J Med Virol. 2021 Mar 5. doi: 10.1002/jmv.26917. Online ahead of print.

ABSTRACT

Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID-19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with SARS-CoV-2. Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 µM; MTT assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 µM). Remdesivir inhibited viral replication with an EC50 = 0.4 µM. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10 , as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3-log10 drop and >4-log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. Itraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15). This article is protected by copyright. All rights reserved.

PMID:33666253 | DOI:10.1002/jmv.26917

EMBO Mol Med. 2021 Mar 5:e12461. doi: 10.15252/emmm.202012461. Online ahead of print.

ABSTRACT

By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

PMID:33665961 | DOI:10.15252/emmm.202012461

iScience. 2021 Feb 5;24(3):102148. doi: 10.1016/j.isci.2021.102148. eCollection 2021 Mar 19.

ABSTRACT

RNA viruses are responsible for many zoonotic diseases that post great challenges for public health. Effective therapeutics against these viral infections remain limited. Here, we deployed a computational framework for host-based drug repositioning to predict potential antiviral drugs from 2,352 approved drugs and 1,062 natural compounds embedded in herbs of traditional Chinese medicine. By systematically interrogating public genetic screening data, we comprehensively cataloged host dependency genes (HDGs) that are indispensable for successful viral infection corresponding to 10 families and 29 species of RNA viruses. We then utilized these HDGs as potential drug targets and interrogated extensive drug-target interactions through database retrieval, literature mining, and de novo prediction using artificial intelligence-based algorithms. Repurposed drugs or natural compounds were proposed against many viral pathogens such as coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses, and influenza viruses. This study helps to prioritize promising drug candidates for in-depth evaluation against these virus-related diseases.

PMID:33665567 | PMC:PMC7900436 | DOI:10.1016/j.isci.2021.102148

Bull Cancer. 2021 Feb 20:S0007-4551(21)00068-0. doi: 10.1016/j.bulcan.2020.12.009. Online ahead of print.

NO ABSTRACT

PMID:33663776 | DOI:10.1016/j.bulcan.2020.12.009

Comput Biol Med. 2021 Feb 24;131:104295. doi: 10.1016/j.compbiomed.2021.104295. Online ahead of print.

ABSTRACT

Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral replication and provide treatment options for COVID-19. Due to the dynamic nature of its binding site loop, PLpro multiple conformations were generated through a long-range 1 micro-second molecular dynamics (MD) simulation. Clustering the MD trajectory enabled us to extract representative structures for the conformational space generated. Adding to the MD representative structures, X-ray structures were involved in an ensemble docking approach to screen the FDA approved drugs for a drug repositioning endeavor. Guided by our recent benchmarking study of SARS-CoV-2 PLpro, FRED docking software was selected for such a virtual screening task. The results highlighted potential consensus binders to many of the MD clusters as well as the newly introduced X-ray structure of PLpro complexed with a small molecule. For instance, three drugs Benserazide, Dobutamine and Masoprocol showed a superior consensus enrichment against the PLpro conformations. Further MD simulations for these drugs complexed with PLpro suggested the superior stability and binding of dobutamine and masoprocol inside the binding site compared to Benserazide. Generally, this approach can facilitate identifying drugs for repositioning via targeting multiple conformations of a crucial target for the rapidly emerging COVID-19 pandemic.

PMID:33662683 | DOI:10.1016/j.compbiomed.2021.104295

Life Sci. 2021 Mar 1:119306. doi: 10.1016/j.lfs.2021.119306. Online ahead of print.

ABSTRACT

AIMS: The present study aims to target the quorum sensing (QS) accessory gene regulator A (AgrA) of Staphylococcus aureus to curtail bacterial virulence through drug repurposing approach.

MAIN METHODS: In silico screening of chemical ligands that bind specifically to the S. aureus C-LytTR domain of AgrA (AgrAC) was carried out. AgrA inhibition and downregulation of virulence genes linked to QS system of S. aureus were determined. Efficacy, dermal toxicity and drug tolerance induction were tested in Balb/C mice dermonecrosis model.

KEY FINDINGS: Bumetanide bound to the conserved amino acid Tyr-229 of AgrA and showed 70% AgrA inhibition at 0.1 μM. Highly significant reduction in the expression of representative virulence genes such as alpha-hemolysin (~5 log2-fold), phenol-soluble modulins (~4 log2-fold) and panton-valentine leukocidin (~3 log2-fold) was noted in vitro. In vivo studies signified bumetanide to be highly effective in controlling the ulcer development and promoted wound healing. Also, the tested substance did not have dermal toxicity and no tolerance induction as well.

SIGNIFICANCE: Targeting the QS regulators could be a possible alternative approach to curtail virulence in S. aureus. In addition, if the QS inhibitors are repurposed it could accelerate the drug development process and reduce the cost. The identified drug bumetanide inhibited AgrA and the results were in comparable to that of a known virulence inhibitor, diflunisal. The newly reported results of bumetanide in this study are expected to mark the drug's visibility for antibiotic adjunctive therapy and topical drug formulations for skin infections research.

PMID:33662434 | DOI:10.1016/j.lfs.2021.119306

Eur J Clin Pharmacol. 2021 Mar 4. doi: 10.1007/s00228-021-03108-x. Online ahead of print.

ABSTRACT

AIMS: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications.

SUBJECT AND METHOD: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, "SARS-CoV-2," "COVID-19," "antivirals," "therapy"), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19.

RESULTS: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir.

DISCUSSION: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.

PMID:33660020 | DOI:10.1007/s00228-021-03108-x

Front Genet. 2021 Feb 15;12:638330. doi: 10.3389/fgene.2021.638330. eCollection 2021.

ABSTRACT

Alzheimer's disease (AD) is a common neurodegenerative dementia in the elderly. Although there is no effective drug to treat AD, proteins associated with AD have been discovered in related studies. One of the proteins is mitochondrial fusion protein 2 (Mfn2), and its regulation presumably be related to AD. However, there is no specific drug for Mfn2 regulation. In this study, a three-tunnel deep neural network (3-Tunnel DNN) model is constructed and trained on the extended Davis dataset. In the prediction of drug-target binding affinity values, the accuracy of the model is up to 88.82% and the loss value is 0.172. By ranking the binding affinity values of 1,063 approved drugs and small molecular compounds in the DrugBank database, the top 15 drug molecules are recommended by the 3-Tunnel DNN model. After removing molecular weight <200 and topical drugs, a total of 11 drug molecules are selected for literature mining. The results show that six drugs have effect on AD, which are reported in references. Meanwhile, molecular docking experiments are implemented on the 11 drugs. The results show that all of the 11 drug molecules could dock with Mfn2 successfully, and 5 of them have great binding effect.

PMID:33659028 | PMC:PMC7917248 | DOI:10.3389/fgene.2021.638330

Ther Deliv. 2021 Mar 4. doi: 10.4155/tde-2021-0009. Online ahead of print.

NO ABSTRACT

PMID:33657869 | DOI:10.4155/tde-2021-0009

Heliyon. 2021 Feb;7(2):e06284. doi: 10.1016/j.heliyon.2021.e06284. Epub 2021 Feb 25.

ABSTRACT

The COVID-19 situation had escalated into an unprecedented global crisis in just a few weeks. On the 30th of January 2020, World Health Organization officially declared the COVID-19 epidemic as a public health emergency of international concern. The confirmed cases were reported to exceed 105,856,046 globally, with the death toll of above 2,311,048, according to the dashboard from Johns Hopkins University on the 7th of February, 2021, though the actual figures may be much higher. Conserved regions of the South Asian strains were used to construct a phylogenetic tree to find evolutionary relationships among the novel virus. Off target similarities were searched with other microorganisms that have been previously reported using Basic Local Alignment Search Tool (BLAST). The conserved regions did not match with any previously reported microorganisms or viruses, which confirmed the novelty of SARS-CoV-2. Currently there is no approved drug for the prevention and treatment of COVID-19, but researchers globally are attempting to come up with one or more soon. Therapeutic strategies need to be addressed urgently to combat COVID-19. Successful drug repurposing is a tool that uses old and safe drugs, is time effective and requires lower development costs, and was thus considered for the study. Molecular docking was used for repurposing drugs from our own comprehensive database of approximately 300 highly characterized, existing drugs with known safety profile, to identify compounds that will inhibit the chosen molecular targets - SARS-CoV-2, ACE2, and TMPRSS2. The study has identified and proposed twenty seven candidates for further in vitro and in vivo studies for the treatment of SARS-CoV-2 infection.

PMID:33655082 | PMC:PMC7906017 | DOI:10.1016/j.heliyon.2021.e06284

Pharmaceuticals (Basel). 2021 Feb 26;14(3):191. doi: 10.3390/ph14030191.

ABSTRACT

Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPKα and MEK/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our results, through combining a clinical cohort analysis with an in vitro study, demonstrate that metformin can be used for drug repositioning in the treatment of DM patients with hypopharyngeal cancer.

PMID:33652909 | DOI:10.3390/ph14030191

J Med Chem. 2021 Mar 2. doi: 10.1021/acs.jmedchem.0c01180. Online ahead of print.

ABSTRACT

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but an effective targeted therapy has not been well-established so far. Considering the lack of effective targets, where do we go next in the current TNBC drug development? A promising intervention for TNBC might lie in de novo small-molecule drugs that precisely target different molecular characteristics of TNBC. However, an ideal single-target drug discovery still faces a huge challenge. Alternatively, other new emerging strategies, such as dual-target drug, drug repurposing, and combination strategies, may provide new insight into the improvement of TNBC therapeutics. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in TNBC therapy, including single-target drugs, dual-target drugs, as well as drug repurposing and combination strategies that will together shed new light on the future directions targeting TNBC vulnerabilities with small-molecule drugs for future therapeutic purposes.

PMID:33650861 | DOI:10.1021/acs.jmedchem.0c01180

Inform Med Unlocked. 2021 Feb 25:100541. doi: 10.1016/j.imu.2021.100541. Online ahead of print.

ABSTRACT

BACKGROUND: Different approaches have been proved effective for combating the COVID-19 pandemic. Accordingly, in silico drug repurposing strategy, has been highly regarded as an accurate computational tool to achieve fast and reliable results. Considering SARS-CoV-2's structural proteins and their interaction the host's cell-specific receptors, this study investigated a drug repurposing strategy aiming to screen compatible inhibitors of FDA-approved drugs against viral entry receptors (ACE2 and CD147) and integral enzyme of the viral polymerase (RdRp).

METHODS: The study screened the FDA-approved drugs against ACE2, CD147, and RDRP by virtual screening and molecular dynamics (MD) simulation.

RESULTS: The results of this study indicated that five drugs with ACE2, four drugs with RDRP , and seven drugs with CD147 achieved the most favorable free binding energy (ΔG < -10). This study selected these drugs for MD simulation investigation whose results demonstrated that ledipasvir with ACE2, estradiol benzoate with CD147, and vancomycin with RDRP represented the most favorable ΔG. Also, paritaprevir and vancomycin have good binding energy with both targets (ACE2 and RdRp).

CONCLUSIONS: Ledipasvir, estradiol benzoate, and vancomycin and paritaprevir are potentially suitable candidates for further investigation as possible treatments of COVID-19 and novel drug development.

PMID:33649734 | PMC:PMC7904474 | DOI:10.1016/j.imu.2021.100541

J Drug Deliv Sci Technol. 2021 Feb 24:102430. doi: 10.1016/j.jddst.2021.102430. Online ahead of print.

ABSTRACT

INTRODUCTION: The outbreak of the disease caused by the new coronavirus (COVID-19) has been affecting society's routine and its patterns of interaction worldwide, in addition to the impact on the global economy. To date, there is still no clinically effective treatment for this comorbidity, and drug repositioning might be a good strategy considering the established clinical safety profile. In this context, since COVID-19 affects the respiratory tract, a promising approach would be the pulmonary drug delivery.

OBJECTIVE: Identify repurposing drug candidates for the treatment of COVID-19 based on the data of ongoing clinical trials and in silico studies and also assess their potential to be applied in formulations for pulmonary administration.

METHOD: A narrative literature review was conducted between June and July 2020, by extracting the results from Clinical Trials, PubMed, Web of Science and Science Direct databases.

RESULTS: By crossing the results obtained from diverse sources, 21 common drugs were found, from which only 4 drugs presented studies of pulmonary release formulations, demonstrating the need for greater investment and incentive in this field.

CONCLUSION: Even though the lung is a target that facilitates viral infection and replication, formulations for pulmonary delivery of suitable drugs are still lacking for COVID-19 treatment. However, it is indisputable that the pandemic constitutes a concrete demand, with a profound impact on public health, and that, with the appropriate investments, it will give the pharmaceutical industry an opportunity to reinforce the pulmonary delivery field.

PMID:33649708 | PMC:PMC7903910 | DOI:10.1016/j.jddst.2021.102430

Med Res Rev. 2021 Mar 1. doi: 10.1002/med.21798. Online ahead of print.

ABSTRACT

The Mycobacterium abscessus complex is a group of emerging pathogens that are difficult to treat. There are no effective drugs for successful M. abscessus pulmonary infection therapy, and existing drug regimens recommended by the British or the American Thoracic Societies are associated with poor clinical outcomes. Therefore, novel antibacterial drugs are urgently needed to contain this global threat. The current anti-M. abscessus small-molecule drug development process can be enhanced by two parallel strategies-discovery of compounds from new chemical classes and commercial drug repurposing. This review focuses on recent advances in the finding of novel small-molecule agents, and more particularly focuses on the activity, mode of action and structure-activity relationship of promising inhibitors from five different chemical classes-benzimidazoles, indole-2-carboxamides, benzothiazoles, 4-piperidinoles, and oxazolidionones. We further discuss some other interesting small molecules, such as thiacetazone derivatives and benzoboroxoles, that are in the early stages of drug development, and summarize current knowledge about the efficacy of repurposable drugs, such as rifabutin, tedizolid, bedaquiline, and others. We finally review targets of therapeutic interest in M. abscessus that may be worthy of future drug and adjunct therapeutic development.

PMID:33645845 | DOI:10.1002/med.21798

J Clin Pharm Ther. 2021 Mar 1. doi: 10.1111/jcpt.13390. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Infection by SARS-CoV-2, the virus responsible of COVID-19, is associated with limited treatment options. The purpose of this study was to evaluate the rationale for repurposing functional inhibitors of acid sphingomyelinase (FIASMAs), several of which are approved medicines, for the treatment of SAR-CoV-2 infections.

COMMENT: We propose and discuss the FIASMAs' lysosomotropism as a possible explanation for their observed in vitro activities against viruses, and more specifically against infections caused by coronaviruses such as SARS-CoV-2. Successful in vitro-to-in vivo translation of FIASMAs requires that their pharmacokinetics (dosing regimen and drug-drug interactions) are matched with viral kinetics.

WHAT IS NEW AND CONCLUSION: Drug repurposing to ensure rapid patient access to effective treatment has garnered much attention in this era of the COVID-19 pandemic. The observed lysosomotropic activity of small-molecule FIASMA compounds suggests that their repurposing as potential drugs against SARS-CoV-2 is promising.

PMID:33645763 | DOI:10.1111/jcpt.13390

Yakugaku Zasshi. 2021;141(3):315-321. doi: 10.1248/yakushi.20-00179-2.

ABSTRACT

Gold compounds have been employed throughout history to treat various types of disease, from ancient times to the present day. In the year 1985, auranofin, a gold-containing compound, was approved by U.S. Food and Drug Administration (FDA) as a therapeutic agent to target rheumatoid arthritis that would facilitate easy oral drug administration as opposed to conventional intramuscular injection used in treatments. Furthermore, auranofin demonstrates promising results for the treatment of various diseases beyond rheumatoid arthritis, including cancer, neurodegenerative diseases, acquired immune deficiency syndrome, and bacterial and parasitic infections. Various potential novel applications for auranofin have been proposed for treating human diseases. Auranofin has previously been demonstrated to inhibit thioredoxin reductase (TrxR) involved within the thioredoxin (Trx) system that comprises one of the critical cellular redox systems within the body. TrxR comprises the sole known enzyme that catalyzes Trx reduction. With cancers in particular, TrxR inhibition facilitates an increase in cellular oxidative stress and suppresses tumor growth. In this review, we describe the potential of auranofin to serve as an anticancer agent and further drug repurposing to utilize this as a strategy for further appropriate drug developments.

PMID:33642497 | DOI:10.1248/yakushi.20-00179-2