World J Gastroenterol. 2021 Nov 14;27(42):7210-7232. doi: 10.3748/wjg.v27.i42.7210.

ABSTRACT

Clostridioides difficile (C. difficile) is a gram-positive, anaerobic spore-forming bacterium and a major cause of antibiotic-associated diarrhea. Humans are naturally resistant to C. difficile infection (CDI) owing to the protection provided by healthy gut microbiota. When the gut microbiota is disturbed, C. difficile can colonize, produce toxins, and manifest clinical symptoms, ranging from asymptomatic diarrhea and colitis to death. Despite the steady-if not rising-prevalence of CDI, it will certainly become more problematic in a world of antibiotic overuse and the post-antibiotic era. C. difficile is naturally resistant to most of the currently used antibiotics as it uses multiple resistance mechanisms. Therefore, current CDI treatment regimens are extremely limited to only a few antibiotics, which include vancomycin, fidaxomicin, and metronidazole. Therefore, one of the main challenges experienced by the scientific community is the development of alternative approaches to control and treat CDI. In this Frontier article, we collectively summarize recent advances in alternative treatment approaches for CDI. Over the past few years, several studies have reported on natural product-derived compounds, drug repurposing, high-throughput library screening, phage therapy, and fecal microbiota transplantation. We also include an update on vaccine development, pre- and pro-biotics for CDI, and toxin antidote approaches. These measures tackle CDI at every stage of disease pathology via multiple mechanisms. We also discuss the gaps and concerns in these developments. The next epidemic of CDI is not a matter of if but a matter of when. Therefore, being well-equipped with a collection of alternative therapeutics is necessary and should be prioritized.

PMID:34876784 | PMC:PMC8611198 | DOI:10.3748/wjg.v27.i42.7210

Pharmacopsychiatry. 2021 Dec 7. doi: 10.1055/a-1686-9620. Online ahead of print.

ABSTRACT

Serotonin reuptake inhibitors (SRIs) are safe and widely used for a variety of indications including depressive disorders, anxiety, and chronic pain. Besides inhibiting the serotonin transporter, these medications have broad-spectrum properties in many systems. Their roles have been studied in cancer, Alzheimer's disease, and infectious processes. The COVID-19 pandemic highlighted the importance of drug repurposing of medications already in use. We conducted a narrative review of current evidence and ongoing research on drug repurposing of SRIs, with a focus on immunomodulatory, antiproliferative, and neuroprotective activity. SRIs may have clinical use as repurposed agents for a wide variety of conditions including but not limited to COVID-19, Alzheimer's disease, and neoplastic processes. Further research, particularly randomized controlled trials, will be necessary to confirm the utility of SRIs for new indications.

PMID:34875696 | DOI:10.1055/a-1686-9620

Int J Parasitol Drugs Drug Resist. 2021 Nov 25;17:204-212. doi: 10.1016/j.ijpddr.2021.10.003. Online ahead of print.

ABSTRACT

Naegleria fowleri is both a pathogenic and a free-living microbial eukaryote, responsible for the development of primary amoebic meningoencephalitis (PAM) in humans. PAM is a rapid, severe and fatal underestimated infectious disease, which has been reported in countries with warmer climates. The major drawbacks with PAM are the lack of effective therapies and delay in diagnosis. The current frontline treatment presents a low rate of recovery (5%) and severe adverse effects. For example, many drug candidates lack efficacy, since they do not effectively cross the blood-brain-barrier. Consequently, more effective drugs are urgently needed. Herein, we report a new in vitro method suitable for medium- and high-throughput drug discovery assays, using the closely related Naegleria gruberi as a model. We have subsequently used this method to screen a library of 1175 Food and Drug Administration-approved drugs. As a result, we present three drugs (camptothecin, pyrimethamine, and terbinafine) that can be repurposed, and are anticipated to readily cross the blood-brain-barrier with activity against Naegleria species in therapeutically achievable concentrations. Successively, we integrated several in vitro assays that resulted in identifying fast-acting and high amoebicidal drugs. In conclusion, we present a new approach for the identification of anti-Naegleria drugs along with three potential drug candidates for further development for the treatment of PAM.

PMID:34875573 | DOI:10.1016/j.ijpddr.2021.10.003

Bioorg Med Chem. 2021 Nov 22;53:116523. doi: 10.1016/j.bmc.2021.116523. Online ahead of print.

ABSTRACT

Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir's limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 μM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.

PMID:34875467 | DOI:10.1016/j.bmc.2021.116523

J Ethnopharmacol. 2021 Dec 4:114893. doi: 10.1016/j.jep.2021.114893. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: A mixture (SH003) of Astragalus membranaceus (Fisch.) Bunge, Angelica gigas Nakai, and Trichosanthes Kirilowii (Maxim.) has beneficial effects against several carcinomas. There have been few reports on an immune-enhancing activity of SH003 and its active constituent nodakenin.

AIM OF THE STUDY: This study aimed at identifying the immune-enhancing effect of SH003 and nodakenin.

MATERIALS AND METHODS: The immune-enhancing effect was evaluated using RAW264.7 macrophages, mouse primary splenocytes, and a cyclophosphamide (CP)-induced immunosuppression murine model.

RESULTS: The results show that SH003 or nodakenin stimulated the production levels of granulocyte colony-stimulating factor, IL-12, IL-2, IL-6, TNF-α, and nitric oxide (NO) and the expression levels of iNOS in RAW264.7 macrophages. SH003 or nodakenin also enhanced NF-κB p65 activation in RAW264.7 macrophages. SH003 or nodakenin stimulated the production levels of IFN-γ, IL-12, IL-2, TNF-α, and NO and the expression levels of iNOS in splenocytes. SH003 or nodakenin increased the splenic lymphocyte proliferation and splenic NK cell activity. In addition, SH003 or nodakenin increased the levels of IFN-γ, IL-12, IL-2, IL-6, and TNF-α in the serum and spleen of CP-treated mice, alleviating CP-induced immunosuppression.

CONCLUSION: Taken together, the results of this study show that SH003 improved immunosuppression through the activation of macrophages, splenocytes, and NK cells. These findings suggest that SH003 could be applied as a potential immunostimulatory agent for a variety of diseases caused or exacerbated by immunodeficiency.

PMID:34875347 | DOI:10.1016/j.jep.2021.114893

Bioinformatics. 2021 Dec 7:btab826. doi: 10.1093/bioinformatics/btab826. Online ahead of print.

ABSTRACT

MOTIVATION: Drug repurposing is a potential alternative to the traditional drug discovery process. Drug repurposing can be formulated as a recommender system that recommends novel indications for available drugs based on known drug-disease associations. This paper presents a method based on non-negative matrix factorization (NMF-DR) to predict the drug-related candidate disease indications. This work proposes a recommender system-based method for drug repurposing to predict novel drug indications by integrating drug and diseases related data sources. For this purpose, this framework first integrates two types of disease similarities, the associations between drugs and diseases, and the various similarities between drugs from different views to make a heterogeneous drug-disease interaction network. Then, an improved non-negative matrix factorization-based method is proposed to complete the drug-disease adjacency matrix with predicted scores for unknown drug-disease pairs.

RESULTS: The comprehensive experimental results show that NMF-DR achieves superior prediction performance when compared with several existing methods for drug-disease association prediction.

AVAILABILITY: The program is available at https://github.com/sshaghayeghs/NMF-DR.

PMID:34875000 | DOI:10.1093/bioinformatics/btab826

Curr Res Pharmacol Drug Discov. 2021;2:100042. doi: 10.1016/j.crphar.2021.100042. Epub 2021 Jul 28.

ABSTRACT

It has been said that COVID-19 is a generational challenge in many ways. But, at the same time, it becomes a catalyst for collective action, innovation, and discovery. Realizing the full potential of artificial intelligence (AI) for structure determination of unknown proteins and drug discovery are some of these innovations. Potential applications of AI include predicting the structure of the infectious proteins, identifying drugs that may be effective in targeting these proteins, and proposing new chemical compounds for further testing as potential drugs. AI and machine learning (ML) allow for rapid drug development including repurposing existing drugs. Algorithms were used to search for novel or approved antiviral drugs capable of inhibiting SARS-CoV-2. This paper presents a survey of AI and ML methods being used in various biochemistry of SARS-CoV-2, from structure to drug development, in the fight against the deadly COVID-19 pandemic. It is envisioned that this study will provide AI/ML researchers and the wider community an overview of the current status of AI applications particularly in structural biology, drug repurposing, and development, and motivate researchers in harnessing AI potentials in the fight against COVID-19.

PMID:34870150 | PMC:PMC8317454 | DOI:10.1016/j.crphar.2021.100042

Curr Res Pharmacol Drug Discov. 2021;2:100011. doi: 10.1016/j.crphar.2020.100011. Epub 2020 Dec 11.

ABSTRACT

There are currently no emergency treatments for pandemics, yet drug repositioning has emerged as the foremost treatment development strategy for COVID-19, with an aim to identify successful antiviral therapeutics from safe, non-antiviral candidates. These therapeutics include antibiotics such as azithromycin and the antiparasitic nitazoxanide, both of which exhibit antiviral activity. Broad-spectrum therapeutics (BSTs) are a class of antimicrobials active against multiple pathogen types. Establishment of a developmental framework for BSTs will markedly improve global preparedness for future health emergencies.

PMID:34870144 | PMC:PMC8035643 | DOI:10.1016/j.crphar.2020.100011

Front Microbiol. 2021 Nov 18;12:759817. doi: 10.3389/fmicb.2021.759817. eCollection 2021.

ABSTRACT

The apicomplexan parasite, Theileria annulata, is the most prevalent hemoprotozoan in livestock, causing significant economic losses worldwide. It is essential to develop new and improved therapeutics, as current control measures are compromised by the development of resistance against the only available antitheilerial drug, buparvaquone (BPQ). Histone deacetylase inhibitors (HDACi) were shown to treat cancer effectively and revealed in vitro antiparasitic activity against apicomplexan parasites such as Plasmodium and Toxoplasma. In this study, we investigated the antitheilerial activity of the four anti-cancer HDACi (vorinostat, romidepsin, belinostat, and panobinostat) against the schizont stage of T. annulata parasites. All four HDACi showed potent activity and increased hyperacetylation of the histone-4 protein. However, based on the low host cell cytotoxicity and IC50 values, vorinostat (0.103 μM) and belinostat (0.069 μM) were the most effective showing antiparasitic activity. The parasite-specific activities of the HDACi (vorinostat and belinostat) were evaluated by western blotting using parasite-specific antibodies and in silico analysis. Both vorinostat and belinostat reduced the Theileria infected cell viability by downregulating anti-apoptotic proteins and mitochondrial dysfunction, leading to caspase-dependent cell apoptosis. The HDACi caused irreversible and antiproliferative effects on the Theileria infected cell lines. Our results collectively showed that vorinostat and belinostat could be used as an alternative therapy for treating Theileria parasites.

PMID:34867888 | PMC:PMC8640587 | DOI:10.3389/fmicb.2021.759817

Front Endocrinol (Lausanne). 2021 Nov 18;12:711906. doi: 10.3389/fendo.2021.711906. eCollection 2021.

ABSTRACT

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides that contribute to the regulation of intestinal motility and secretion, exocrine and endocrine secretions, and homeostasis of the immune system. Their biological effects are mediated by three receptors named VPAC1, VPAC2 and PAC1 that belong to class B GPCRs. VIP and PACAP receptors have been identified as potential therapeutic targets for the treatment of chronic inflammation, neurodegenerative diseases and cancer. However, pharmacological use of endogenous ligands for these receptors is limited by their lack of specificity (PACAP binds with high affinity to VPAC1, VPAC2 and PAC1 receptors while VIP recognizes both VPAC1 and VPAC2 receptors), their poor oral bioavailability (VIP and PACAP are 27- to 38-amino acid peptides) and their short half-life. Therefore, the development of non-peptidic small molecules or specific stabilized peptidic ligands is of high interest. Structural similarities between VIP and PACAP receptors are major causes of difficulties in the design of efficient and selective compounds that could be used as therapeutics. In this study we performed structure-based virtual screening against the subset of the ZINC15 drug library. This drug repositioning screen provided new applications for a known drug: ticagrelor, a P2Y12 purinergic receptor antagonist. Ticagrelor inhibits both VPAC1 and VPAC2 receptors which was confirmed in VIP-binding and calcium mobilization assays. A following analysis of detailed ticagrelor binding modes to all three VIP and PACAP receptors with molecular dynamics revealed its allosteric mechanism of action. Using a validated homology model of inactive VPAC1 and a recently released cryo-EM structure of active VPAC1 we described how ticagrelor could block conformational changes in the region of 'tyrosine toggle switch' required for the receptor activation. We also discuss possible modifications of ticagrelor comparing other P2Y12 antagonist - cangrelor, closely related to ticagrelor but not active for VPAC1/VPAC2. This comparison with inactive cangrelor could lead to further improvement of the ticagrelor activity and selectivity for VIP and PACAP receptor sub-types.

PMID:34867774 | PMC:PMC8637020 | DOI:10.3389/fendo.2021.711906

Front Pharmacol. 2021 Nov 10;12:790952. doi: 10.3389/fphar.2021.790952. eCollection 2021.

NO ABSTRACT

PMID:34867425 | PMC:PMC8635986 | DOI:10.3389/fphar.2021.790952

Front Pharmacol. 2021 Nov 18;12:704205. doi: 10.3389/fphar.2021.704205. eCollection 2021.

ABSTRACT

SARS-CoV-2 has spread across the globe in no time. In the beginning, people suffered due to the absence of efficacious drugs required to treat severely ill patients. Nevertheless, still, there are no established therapeutic molecules against the SARS-CoV-2. Therefore, repurposing of the drugs started against SARS-CoV-2, due to which several drugs were approved for the treatment of COVID-19 patients. This paper reviewed the treatment regime for COVID-19 through drug repurposing from December 8, 2019 (the day when WHO recognized COVID-19 as a pandemic) until today. We have reviewed all the clinical trials from RECOVERY trials, ACTT-1 and ACTT-2 study group, and other major clinical trial platforms published in highly reputed journals such as NEJM, Lancet, etc. In addition to single-molecule therapy, several combination therapies were also evaluated to understand the treatment of COVID-19 from these significant clinical trials. To date, several lessons have been learned on the therapeutic outcomes for COVID-19. The paper also outlines the experiences gained during the repurposing of therapeutic molecules (hydroxychloroquine, ritonavir/ lopinavir, favipiravir, remdesivir, ivermectin, dexamethasone, camostatmesylate, and heparin), immunotherapeutic molecules (tocilizumab, mavrilimumab, baricitinib, and interferons), combination therapy, and convalescent plasma therapy to treat COVID-19 patients. We summarized that anti-viral therapeutic (remdesivir) and immunotherapeutic (tocilizumab, dexamethasone, and baricitinib) therapy showed some beneficial outcomes. Until March 2021, 4952 clinical trials have been registered in ClinicalTrials.gov toward the drug and vaccine development for COVID-19. More than 100 countries have participated in contributing to these clinical trials. Other than the registered clinical trials (medium to large-size), several small-size clinical trials have also been conducted from time to time to evaluate the treatment of COVID-19. Four molecules showed beneficial therapeutic to treat COVID-19 patients. The short-term repurposing of the existing drug may provide a successful outcome for COVID-19 patients. Therefore, more clinical trials can be initiated using potential anti-viral molecules by evaluating in different phases of clinical trials.

PMID:34867318 | PMC:PMC8636940 | DOI:10.3389/fphar.2021.704205

J Microbiol Biotechnol. 2021 Dec 1;32(1). doi: 10.4014/jmb.2110.10029. Online ahead of print.

ABSTRACT

Diagnostics, vaccines and drugs are indispensable tools and control measures in order to overcome infectious diseases such as coronavirus disease 2019 (COVID-19). Diagnostic tools based on RT-PCR were developed early in the COVID-19 pandemic, which were urgently required for quarantine (test, trace and isolation). Vaccines were also successfully developed using new platform technologies such as mRNA vaccines and virus-vectored vaccines within one year after identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a causative agent of COVID-19. Drug development has been conducted in various ways including drug repurposing, convalescent plasma therapy, and monoclonal antibody development. Among all these efforts, COVID-19 drug development will be reviewed along with upcoming challenges.

PMID:34866128 | DOI:10.4014/jmb.2110.10029

Brief Bioinform. 2021 Dec 2:bbab490. doi: 10.1093/bib/bbab490. Online ahead of print.

ABSTRACT

To better understand the potential of drug repurposing in COVID-19, we analyzed control strategies over essential host factors for SARS-CoV-2 infection. We constructed comprehensive directed protein-protein interaction (PPI) networks integrating the top-ranked host factors, the drug target proteins and directed PPI data. We analyzed the networks to identify drug targets and combinations thereof that offer efficient control over the host factors. We validated our findings against clinical studies data and bioinformatics studies. Our method offers a new insight into the molecular details of the disease and into potentially new therapy targets for it. Our approach for drug repurposing is significant beyond COVID-19 and may be applied also to other diseases.

PMID:34864885 | DOI:10.1093/bib/bbab490

Bioinformatics. 2021 Dec 2:btab820. doi: 10.1093/bioinformatics/btab820. Online ahead of print.

ABSTRACT

MOTIVATION: Drug repositioning that aims to find new indications for existing drugs has been an efficient strategy for drug discovery. In the scenario where we only have confirmed disease-drug associations as positive pairs, a negative set of disease-drug pairs is usually constructed from the unknown disease-drug pairs in previous studies, where we do not know whether drugs and diseases can be associated, to train a model for disease-drug association prediction (drug repositioning). Drugs and diseases in these negative pairs can potentially be associated, but most studies have ignored them.

RESULTS: We present a method, springD2A, to capture the uncertainty in the negative pairs, and to discriminate between positive and unknown pairs because the former are more reliable. In springD2A, we introduce a spring-like penalty for the loss of negative pairs, which is strong if they are too close in a unit sphere, but mild if they are at a moderate distance. We also design a sequential sampling in which the probability of an unknown disease-drug pair sampled as negative is proportional to its score predicted as positive. Multiple models are learned during sequential sampling, and we adopt parameter- and feature-based ensemble schemes to boost performance. Experiments show springspringD2A is an effective tool for drug-repositioning.

AVAILABILITY: A python implementation of springD2A and datasets used in this study are available at https://github.com/wangyuanhao/springD2A.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:34864881 | DOI:10.1093/bioinformatics/btab820

Brief Bioinform. 2021 Dec 2:bbab511. doi: 10.1093/bib/bbab511. Online ahead of print.

ABSTRACT

Drug repositioning is proposed to find novel usages for existing drugs. Among many types of drug repositioning approaches, predicting drug-drug interactions (DDIs) helps explore the pharmacological functions of drugs and achieves potential drugs for novel treatments. A number of models have been applied to predict DDIs. The DDI network, which is constructed from the known DDIs, is a common part in many of the existing methods. However, the functions of DDIs are different, and thus integrating them in a single DDI graph may overlook some useful information. We propose a graph convolutional network with multi-kernel (GCNMK) to predict potential DDIs. GCNMK adopts two DDI graph kernels for the graph convolutional layers, namely, increased DDI graph consisting of 'increase'-related DDIs and decreased DDI graph consisting of 'decrease'-related DDIs. The learned drug features are fed into a block with three fully connected layers for the DDI prediction. We compare various types of drug features, whereas the target feature of drugs outperforms all other types of features and their concatenated features. In comparison with three different DDI prediction methods, our proposed GCNMK achieves the best performance in terms of area under receiver operating characteristic curve and area under precision-recall curve. In case studies, we identify the top 20 potential DDIs from all unknown DDIs, and the top 10 potential DDIs from the unknown DDIs among breast, colorectal and lung neoplasms-related drugs. Most of them have evidence to support the existence of their interactions. fangxiang.wu@usask.ca.

PMID:34864856 | DOI:10.1093/bib/bbab511

Biomed Pharmacother. 2021 Dec 1:112375. doi: 10.1016/j.biopha.2021.112375. Online ahead of print.

ABSTRACT

Breast cancer (BC) is mostly observed in women and is responsible for huge mortality in women subjects globally. Due to the continued development of drug resistance and other contributing factors, the scientific community needs to look for new alternatives, and drug repurposing is one of the best opportunities. Here we light upon the drug repurposing with a major focus on breast cancer. BC is a division of cancer known as the leading cause of death of 2.3 million women globally, with 685,000 fatalities. This number is steadily rising, necessitating the development of a treatment that can extend survival time. All available treatments for BC are very costly as well as show side effects. This unfulfilled requirement of the anti-cancer drugs ignited an enthusiasm for drug repositioning, which means finding out the anti-cancer use of already marketed drugs for other complications. With the advancement in proteomics, genomics, and computational approaches, the drug repurposing process hastens. So many drugs are repurposed for the BC, including alkylating agents, antimetabolite, anthracyclines, an aromatase inhibitor, mTOR, and many more. The drug resistance in breast cancer is rising, so reviewing how the challenges in breast cancer can be combated with drug repurposing. This paper provides the updated information on all the repurposed drugs candidates for breast cancer with the molecular mechanism responsible for their anti-tumor activity. Additionally, all the challenges that occur during the repurposing of the drugs are discussed.

PMID:34863612 | DOI:10.1016/j.biopha.2021.112375

Sci Rep. 2021 Dec 2;11(1):23315. doi: 10.1038/s41598-021-02432-7.

ABSTRACT

The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.

PMID:34857794 | DOI:10.1038/s41598-021-02432-7

Nat Commun. 2021 Dec 2;12(1):7042. doi: 10.1038/s41467-021-27387-1.

ABSTRACT

Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.

PMID:34857772 | DOI:10.1038/s41467-021-27387-1

Br J Pharmacol. 2021 Dec 2. doi: 10.1111/bph.15763. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: The zinc finger transcription factor Snail is aberrantly activated in many human cancers and strongly associated with poor prognosis. As a transcription factor, Snail has been traditionally considered an "undruggable" target. Here, we identified a potent small molecule inhibitor of Snail, namely trimethoprim, and investigated its potential antitumor effects and the underlying mechanisms.

EXPERIMENTAL APPROACH: The inhibitory action of trimethoprim on Snail protein and the related molecular mechanisms were revealed by molecular docking, biolayer interferometry, immunoblotting, immunoprecipitation, qRT-PCR, pull-down, and cycloheximide pulse-chase assays. The anti-proliferative and anti-metastatic effects of trimethoprim via targeting Snail were tested in multiple cell-based assays and animal models.

KEY RESULTS: This study identified trimethoprim, an antimicrobial drug, as a potent anti-tumor agent via targeting Snail. Molecular modeling analysis predicted that trimethoprim directly binds to the arginine-174 pocket of Snail protein. We further discovered that trimethoprim strongly interrupts the interaction of Snail with CREB-binding protein (CBP)/p300, which consequently suppresses Snail acetylation and promotes Snail degradation through ubiquitin-proteasome pathway. Furthermore, trimethoprim sufficiently inhibited the proliferation, epithelial-mesenchymal transition (EMT), and migration of cancer cells in vitro via specifically targeting Snail. More importantly, trimethoprim effectively reduced Snail-driven tumor growth and metastasis to vital organs such as lung, bone, and liver.

CONCLUSIONS AND IMPLICATIONS: These findings indicate, for the first time, that trimethoprim suppresses tumor growth and metastasis via targeting Snail. This study provides insights for a better understanding of the anticancer effects of trimethoprim and offers a potential anti-cancer therapeutic agent for clinical treatment.

PMID:34855201 | DOI:10.1111/bph.15763