Curr Res Microb Sci. 2024 May 15;6:100242. doi: 10.1016/j.crmicr.2024.100242. eCollection 2024.

ABSTRACT

Mucormycosis is a severe fungal infection that demands immediate and decisive intervention upon suspicion. The causative agents of mucormycosis exhibit inherent resistance to echinocandins and voriconazole, and their in vitro susceptibility to terbinafine is highly variable and species-specific. Considering these factors and the limitations of currently available antifungal therapies, the identification of novel antifungals with potent activity against mucormycosis is of paramount importance. This study aims to identify compounds from the MMV Pathogen Box® presenting antifungal activity against selected mucormycosis agents and to evaluate their potential synergistic effects when combined with antifungal drugs. A screening of the Pathogen Box® compounds was conducted, isolated or in combination with sub-inhibitory concentrations of amphotericin B, isavuconazole or posaconazole, against a Rhizopus oryzae strain. Hits from the screenings were further evaluated against eight Mucoralean strains for minimal inhibitory and fungicidal concentration determinations and to confirm synergistic interactions using the checkerboard method. Ultrastructural studies were performed using scanning electron microscopy. MMV675968 exhibited fungicidal activity against a R. oryzae strain. All but one Rhizopus spp. strains presented MIC ≤ 1 μg/mL, with a geometric mean of 0.78 μg/mL observed across all isolates for this compound, which did not change significantly the cellular structure of this fungus. The combination screening with antifungal drugs revealed six additional compounds potentially active against the R. oryzae strain, two of them demonstrated proven synergism through the checkerboard assay. This first study with the MMV Pathogen Box® and Zigomycetes highlights promising new treatment options for mucormycosis in the future.

PMID:38799088 | PMC:PMC11126940 | DOI:10.1016/j.crmicr.2024.100242

Narra J. 2024 Apr;4(1):e319. doi: 10.52225/narra.v4i1.319. Epub 2024 Apr 30.

ABSTRACT

Numerous prior studies have identified therapeutic targets that could effectively combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including the angiotensin-converting enzyme 2 (ACE2) receptor, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). In parallel, antiviral compounds like abacavir, acyclovir, adefovir, amantadine, amprenavir, darunavir, didanosine, oseltamivir, penciclovir, and tenofovir are under investigation for their potential in drug repurposing to address this infection. The aim of the study was to determine the effect of modifying the functional groups of the aforementioned antivirals in silico. Using the genetic optimization for ligand docking algorithm on software Maestro (version 11.1), the modified antivirals were docked onto ACE2 receptor, RdRp, and Mpro. Using QuickProp (Maestro v11.1), PASS (prediction of activity spectra for the substances), and altogether with SwissADME, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) of the modified antivirals, as well as their bioavailability and the predicted activity spectra, were determined. Discovery studio software was used to undertake post-docking analysis. Among the 10 antivirals, N(CH3)2 derivative of darunavir, N(CH3)2 derivative of amprenavir and NCH3 derivative of darunavir exhibited best binding affinities with ACE2 receptor (docking scores: -10.333, -9.527 and -9.695 kJ/mol, respectively). Moreover, NCH3 derivative of abacavir (-6.506 kJ/mol), NO2 derivative of didanosine (-6.877 kJ/mol), NCH3 derivative of darunavir (-7.618 kJ/mol) exerted promising affinity to Mpro. In conclusion, the results of the in silico screenings can serve as a useful information for future experimental works.

PMID:38798846 | PMC:PMC11125382 | DOI:10.52225/narra.v4i1.319

Food Chem. 2024 May 22;454:139747. doi: 10.1016/j.foodchem.2024.139747. Online ahead of print.

ABSTRACT

The structure and function of dietary proteins, as well as their subcellular prediction, are critical for designing and developing new drug compositions and understanding the pathophysiology of certain diseases. As a remedy, we provide a subcellular localization method based on feature fusion and clustering for dietary proteins. Additionally, an enhanced PseAAC (Pseudo-amino acid composition) method is suggested, which builds upon the conventional PseAAC. The study initially builds a novel model of representing the food protein sequence by integrating autocorrelation, chi density, and improved PseAAC to better convey information about the food protein sequence. After that, the dimensionality of the fused feature vectors is reduced by using principal component analysis. With prediction accuracies of 99.24% in the Gram-positive dataset and 95.33% in the Gram-negative dataset, respectively, the experimental findings demonstrate the practicability and efficacy of the proposed approach. This paper is basically exploring pseudo-amino acid composition of not any clinical aspect but exploring a pharmaceutical aspect for drug repositioning.

PMID:38797095 | DOI:10.1016/j.foodchem.2024.139747

Biomed Pharmacother. 2024 May 25:116757. doi: 10.1016/j.biopha.2024.116757. Online ahead of print.

NO ABSTRACT

PMID:38797597 | DOI:10.1016/j.biopha.2024.116757

Nutr Cancer. 2024 May 25:1-9. doi: 10.1080/01635581.2024.2358561. Online ahead of print.

ABSTRACT

Considering the established pharmacokinetics and toxicity profiles, drug repurposing has emerged as an alternative therapeutic approach for treating cancer. Mefloquine has previously demonstrated inhibitory effects on multiple cancer types. This study aims to explore the impact of mefloquine on nasopharyngeal carcinoma (NPC). We found that mefloquine, at pharmacologically achievable concentrations, displayed anti-NPC activity while sparing normal counterparts. Mefloquine inhibits proliferation and induces death by reducing the levels of Cyclin A2, Bcl-2, and Bcl-xL. Intriguingly, we observed an increase in the levels of the anti-apoptotic protein Mcl-1. Mefloquine exerts its effects on NPC cells by inducing lysosomal-mediated ROS production, and the heightened expression of Mcl-1 is a consequence of ROS generation in mefloquine-treated NPC cells. The combination of an Mcl-1 inhibitor with mefloquine synergistically inhibits NPC growth in mice without causing substantial toxicity. These findings demonstrate the effectiveness and limited toxicity of mefloquine as a monotherapy and in combination with an Mcl-1 inhibitor. Our research underscores the promise of the mefloquine and Mcl-1 inhibitor combination as a potential treatment for NPC. Additionally, the elevation of Mcl-1 is a compensatory response in cells exposed to oxidative stress, offering a potential target to overcome resistance induced by pro-oxidant therapies.

PMID:38795070 | DOI:10.1080/01635581.2024.2358561

Pharmaceuticals (Basel). 2024 Apr 29;17(5):569. doi: 10.3390/ph17050569.

ABSTRACT

Metastatic castration-resistant prostate cancer (mCRPC) remains a deadly disease due to a lack of efficacious treatments. The reprogramming of cancer metabolism toward elevated glycolysis is a hallmark of mCRPC. Our goal is to identify therapeutics specifically associated with high glycolysis. Here, we established a computational framework to identify new pharmacological agents for mCRPC with heightened glycolysis activity under a tumor microenvironment, followed by in vitro validation. First, using our established computational tool, OncoPredict, we imputed the likelihood of drug responses to approximately 1900 agents in each mCRPC tumor from two large clinical patient cohorts. We selected drugs with predicted sensitivity highly correlated with glycolysis scores. In total, 77 drugs predicted to be more sensitive in high glycolysis mCRPC tumors were identified. These drugs represent diverse mechanisms of action. Three of the candidates, ivermectin, CNF2024, and P276-00, were selected for subsequent vitro validation based on the highest measured drug responses associated with glycolysis/OXPHOS in pan-cancer cell lines. By decreasing the input glucose level in culture media to mimic the mCRPC tumor microenvironments, we induced a high-glycolysis condition in PC3 cells and validated the projected higher sensitivity of all three drugs under this condition (p < 0.0001 for all drugs). For biomarker discovery, ivermectin and P276-00 were predicted to be more sensitive to mCRPC tumors with low androgen receptor activities and high glycolysis activities (AR(low)Gly(high)). In addition, we integrated a protein-protein interaction network and topological methods to identify biomarkers for these drug candidates. EEF1B2 and CCNA2 were identified as key biomarkers for ivermectin and CNF2024, respectively, through multiple independent biomarker nomination pipelines. In conclusion, this study offers new efficacious therapeutics beyond traditional androgen-deprivation therapies by precisely targeting mCRPC with high glycolysis.

PMID:38794139 | DOI:10.3390/ph17050569

Viruses. 2024 Apr 30;16(5):712. doi: 10.3390/v16050712.

ABSTRACT

Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action. Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in in vitro SARS-CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small-molecule binding sites on Spike, it was unclear what the specific mechanism of action was or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor-binding domain (RBD) or N-terminal domain (NTD) and disrupt the S1 receptor-binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most substitutions to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved, with only a few observed substitutions in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over recent VOC mutant strains and/or greater broad-spectrum antiviral activity for other more distantly related coronaviruses.

PMID:38793593 | DOI:10.3390/v16050712

Int J Mol Sci. 2024 May 15;25(10):5381. doi: 10.3390/ijms25105381.

ABSTRACT

Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer drug development, limited success has been obtained and the average number of FDA approvals per year is declining. So, an increasing interest in drug repurposing exists. Metformin (MET) and aspirin (ASP) possess anticancer properties. This work aims to test the effect of these two drugs in combination on colorectal cancer (CRC) cells in vitro. The effects of MET and/or ASP on cell proliferation, viability, migratory ability, anchorage-independent growth ability (colony formation), and nutrient uptake were determined in two (HT-29 and Caco-2) human CRC cell lines. Individually, MET and ASP possessed antiproliferative, cytotoxic, and antimigratory effects and reduced colony formation in HT-29 cells (BRAF- and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PI3KCA)-mutant), although MET did not affect either 3H-deoxy-D-glucose or 14C-butyrate uptake and lactate production, and ASP caused only a small decrease in 14C-butyrate uptake. Moreover, in these cells, the combination of MET and ASP resulted in a tendency to an increase in the cytotoxic effect and in a potentiation of the inhibitory effect on colony formation, although no additive antiproliferative and antimigratory effects, and no effect on nutrient uptake and lactate production were observed. In contrast, MET and ASP, both individually and in combination, were almost devoid of effects on Caco-2 cells (BRAF- and PI3KCA-wild type). We suggest that inhibition of PI3K is the common mechanism involved in the anti-CRC effect of both MET, ASP and their combination and, therefore, that the combination of MET + ASP may especially benefit PI3KCA-mutant CRC cases, which currently have a poor prognostic.

PMID:38791419 | DOI:10.3390/ijms25105381

Int J Mol Sci. 2024 May 13;25(10):5319. doi: 10.3390/ijms25105319.

ABSTRACT

In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, DReAmocracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, DReAmocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease.

PMID:38791356 | DOI:10.3390/ijms25105319

Int J Mol Sci. 2024 May 12;25(10):5267. doi: 10.3390/ijms25105267.

ABSTRACT

Computational drug-repositioning technology is an effective tool for speeding up drug development. As biological data resources continue to grow, it becomes more important to find effective methods to identify potential therapeutic drugs for diseases. The effective use of valuable data has become a more rational and efficient approach to drug repositioning. The disease-drug correlation method (DDCM) proposed in this study is a novel approach that integrates data from multiple sources and different levels to predict potential treatments for diseases, utilizing support-vector regression (SVR). The DDCM approach resulted in potential therapeutic drugs for neoplasms and cardiovascular diseases by constructing a correlation hybrid matrix containing the respective similarities of drugs and diseases, implementing the SVR algorithm to predict the correlation scores, and undergoing a randomized perturbation and stepwise screening pipeline. Some potential therapeutic drugs were predicted by this approach. The potential therapeutic ability of these drugs has been well-validated in terms of the literature, function, drug target, and survival-essential genes. The method's feasibility was confirmed by comparing the predicted results with the classical method and conducting a co-drug analysis of the sub-branch. Our method challenges the conventional approach to studying disease-drug correlations and presents a fresh perspective for understanding the pathogenesis of diseases.

PMID:38791306 | DOI:10.3390/ijms25105267

Int J Mol Sci. 2024 May 10;25(10):5188. doi: 10.3390/ijms25105188.

ABSTRACT

Since the outbreak of COVID-19, researchers have been working tirelessly to discover effective ways to combat coronavirus infection. The use of computational drug repurposing methods and molecular docking has been instrumental in identifying compounds that have the potential to disrupt the binding between the spike glycoprotein of SARS-CoV-2 and human ACE2 (hACE2). Moreover, the pseudovirus approach has emerged as a robust technique for investigating the mechanism of virus attachment to cellular receptors and for screening targeted small molecule drugs. Pseudoviruses are viral particles containing envelope proteins, which mediate the virus's entry with the same efficiency as that of live viruses but lacking pathogenic genes. Therefore, they represent a safe alternative to screen potential drugs inhibiting viral entry, especially for highly pathogenic enveloped viruses. In this review, we have compiled a list of antiviral plant extracts and natural products that have been extensively studied against enveloped emerging and re-emerging viruses by pseudovirus technology. The review is organized into three parts: (1) construction of pseudoviruses based on different packaging systems and applications; (2) knowledge of emerging and re-emerging viruses; (3) natural products active against pseudovirus-mediated entry. One of the most crucial stages in the life cycle of a virus is its penetration into host cells. Therefore, the discovery of viral entry inhibitors represents a promising therapeutic option in fighting against emerging viruses.

PMID:38791226 | DOI:10.3390/ijms25105188

Biomedicines. 2024 May 10;12(5):1059. doi: 10.3390/biomedicines12051059.

ABSTRACT

Vitamin A, an essential micronutrient, is integral to various biological processes crucial for organismal development and maintenance. Dietary sources of vitamin A encompass preformed retinol, retinyl esters, and provitamin A carotenoids. Retinoic acid (RA), a key component, plays pivotal roles in vision, cell proliferation, apoptosis, immune function, and gene regulation. Drug repurposing, an effective strategy for identifying new therapeutic applications for existing drugs, has gained prominence in recent years. This review seeks to provide a comprehensive overview of the current research landscape surrounding retinoids and drug repurposing. The scope of this review encompasses a comprehensive examination of retinoids and their potential for repurposing in various therapeutic contexts. Despite their efficacy in treating dermatological conditions, concerns about toxicity persist, driving the search for safer and more potent retinoids. The molecular mechanisms underlying retinoid activity involve binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), leading to transcriptional regulation of target genes. This review seeks to shed light on the possibilities for repurposing retinoids to cover a wider spectrum of therapeutic uses by exploring recent scientific progress. It also aims to offer a more comprehensive understanding of the therapeutic prospects of retinoids and the broader impact of drug repositioning in contemporary medicine.

PMID:38791021 | DOI:10.3390/biomedicines12051059

Microb Cell Fact. 2024 May 24;23(1):152. doi: 10.1186/s12934-024-02410-4.

ABSTRACT

BACKGROUND: A novel plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the "last-resort" antibiotic tigecycline.

RESULTS: In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance.

CONCLUSION: These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.

PMID:38790017 | DOI:10.1186/s12934-024-02410-4

Prog Mol Biol Transl Sci. 2024;205:247-257. doi: 10.1016/bs.pmbts.2024.03.013. Epub 2024 Apr 16.

ABSTRACT

High-throughput screening (HTS) is a simple, rapid and cost-effective solution to determine active candidates from large library of compounds. HTS is gaining attention from Pharmaceuticals and Biotechnology companies for accelerating their drug discovery programs. Conventional drug discovery program is time consuming and expensive. In contrast drug repurposing approach is cost-effective and increases speed of drug discovery as toxicity profile is already known. The present chapter highlight HTS technology including microplate, microfluidics, lab-on-chip, organ-on-chip for drug repurposing. The current chapter also highlights the application of HTS for bacterial infections and cancer.

PMID:38789182 | DOI:10.1016/bs.pmbts.2024.03.013

Prog Mol Biol Transl Sci. 2024;205:221-245. doi: 10.1016/bs.pmbts.2024.03.027. Epub 2024 Apr 4.

ABSTRACT

Drug repurposing, or drug repositioning, refers to the identification of alternative therapeutic applications for established medications that go beyond their initial indications. This strategy has becoming increasingly popular since it has the potential to significantly reduce the overall costs of drug development by around $300 million. System biology methodologies have been employed to facilitate medication repurposing, encompassing computational techniques such as signature matching and network-based strategies. These techniques utilize pre-existing drug-related data types and databases to find prospective repurposed medications that have minimal or acceptable harmful effects on patients. The primary benefit of medication repurposing in comparison to drug development lies in the fact that approved pharmaceuticals have already undergone multiple phases of clinical studies, thereby possessing well-established safety and pharmacokinetic properties. Utilizing system biology methodologies in medication repurposing offers the capacity to expedite the discovery of viable candidates for drug repurposing and offer novel perspectives for structure-based drug design.

PMID:38789180 | DOI:10.1016/bs.pmbts.2024.03.027

Prog Mol Biol Transl Sci. 2024;205:171-211. doi: 10.1016/bs.pmbts.2024.03.030. Epub 2024 Mar 31.

ABSTRACT

The purpose of drug repurposing is to leverage previously approved drugs for a particular disease indication and apply them to another disease. It can be seen as a faster and more cost-effective approach to drug discovery and a powerful tool for achieving precision medicine. In addition, drug repurposing can be used to identify therapeutic candidates for rare diseases and phenotypic conditions with limited information on disease biology. Machine learning and artificial intelligence (AI) methodologies have enabled the construction of effective, data-driven repurposing pipelines by integrating and analyzing large-scale biomedical data. Recent technological advances, especially in heterogeneous network mining and natural language processing, have opened up exciting new opportunities and analytical strategies for drug repurposing. In this review, we first introduce the challenges in repurposing approaches and highlight some success stories, including those during the COVID-19 pandemic. Next, we review some existing computational frameworks in the literature, organized on the basis of the type of biomedical input data analyzed and the computational algorithms involved. In conclusion, we outline some exciting new directions that drug repurposing research may take, as pioneered by the generative AI revolution.

PMID:38789178 | DOI:10.1016/bs.pmbts.2024.03.030

Braz J Microbiol. 2024 May 24. doi: 10.1007/s42770-024-01344-8. Online ahead of print.

ABSTRACT

Candida albicans is a polymorphic human fungal pathogen and the prime etiological agent responsible for candidiasis. The main two aspects of C. albicans virulence that have been suggested are yeast-to-hyphal (Y-H) morphological transitions and biofilm development. Anti-fungal agents targeting these virulence attributes enhances the antifungal drug development process. Repositioning with other non-fungal drugs offered a one of the new strategies and a potential alternative option to counter the urgent need for antifungal drug development. In the current study, an antiviral drug ganciclovir was screened as an antifungal agent against ATCC 90028, 10231 and clinical isolate (C1). Ganciclovir at 0.5 mg/ml concentration reduced 50% hyphal development on a silicon-based urinary catheter and was visualized using scanning electron microscopy. Ganciclovir reduced ergosterol biosynthesis in both strains and C1 isolate of C. albicans in a concentration-dependent manner. Additionally, a gene expression profile study showed that ganciclovir treatment resulted in upregulation of hyphal-specific repressors MIG1, TUP1, and NRG1 in C. albicans. Additionally, an in vivo study on the Bombyx mori silkworm model further evidenced the virulence inhibitory ability of ganciclovir (0.5 mg/ml) against C. albicans. This is the first report that explore the novel anti-morphogenic activities of ganciclovir against the pathogenic C. albicans strains, along with clinical isolates. Further, ganciclovir may be considered for therapeutic purpose after combinations with standard antifungal agents.

PMID:38789908 | DOI:10.1007/s42770-024-01344-8

EMBO Mol Med. 2024 May 24. doi: 10.1038/s44321-024-00073-7. Online ahead of print.

ABSTRACT

In the injured brain, new neurons produced from endogenous neural stem cells form chains and migrate to injured areas and contribute to the regeneration of lost neurons. However, this endogenous regenerative capacity of the brain has not yet been leveraged for the treatment of brain injury. Here, we show that in healthy brain chains of migrating new neurons maintain unexpectedly large non-adherent areas between neighboring cells, allowing for efficient migration. In instances of brain injury, neuraminidase reduces polysialic acid levels, which negatively regulates adhesion, leading to increased cell-cell adhesion and reduced migration efficiency. The administration of zanamivir, a neuraminidase inhibitor used for influenza treatment, promotes neuronal migration toward damaged regions, fosters neuronal regeneration, and facilitates functional recovery. Together, these findings shed light on a new mechanism governing efficient neuronal migration in the adult brain under physiological conditions, pinpoint the disruption of this mechanism during brain injury, and propose a promising therapeutic avenue for brain injury through drug repositioning.

PMID:38789599 | DOI:10.1038/s44321-024-00073-7

Sci Rep. 2024 May 24;14(1):11890. doi: 10.1038/s41598-024-62684-x.

ABSTRACT

Biofilm-associated candidiasis poses a significant challenge in clinical settings due to the limited effectiveness of existing antifungal treatments. The challenges include increased pathogen virulence, multi-drug resistance, and inadequate penetration of antimicrobials into biofilm structures. One potential solution to this problem involves the development of novel drugs that can modulate fungal virulence and biofilm formation, which is essential for pathogenesis. Resistance in Candida albicans is initiated by morphological changes from yeast to hyphal form. This transition triggers a series of events such as cell wall elongation, increased adhesion, invasion of host tissues, pathogenicity, biofilm formation, and the initiation of an immune response. The cell wall is a critical interface for interactions with host cells, primarily through various cell wall proteins, particularly mannoproteins. Thus, cell wall proteins and enzymes are considered potential antifungal targets. In this regard, we explored α-glucosidase as our potential target which plays a crucial role in processing mannoproteins. Previous studies have shown that inhibition of α-glucosidase leads to defects in cell wall integrity, reduced adhesion, diminished secretion of hydrolytic enzymes, alterations in immune recognition, and reduced pathogenicity. Since α-glucosidase, primarily converts carbohydrates, our study focuses on FDA-approved carbohydrate mimic drugs (Glycomimetics) with well-documented applications in various biological contexts. Through virtual screening of 114 FDA-approved carbohydrate-based drugs, a pseudo-sugar Acarbose, emerged as a top hit. Acarbose is known for its pharmacological potential in managing type 2 diabetes mellitus by targeting α-glucosidase. Our preliminary investigations indicate that Acarbose effectively inhibits C. albicans biofilm formation, reduces virulence, impairs morphological switching, and hinders the adhesion and invasion of host cells, all at very low concentrations in the nanomolar range. Furthermore, transcriptomic analysis reveals the mechanism of action of Acarbose, highlighting its role in targeting α-glucosidase.

PMID:38789465 | DOI:10.1038/s41598-024-62684-x

Prog Mol Biol Transl Sci. 2024;205:91-109. doi: 10.1016/bs.pmbts.2024.03.018. Epub 2024 Apr 4.

ABSTRACT

The drug discovery and development (DDD) process greatly relies on the data available in various forms to generate hypotheses for novel drug design. The complex and heterogeneous nature of biological data makes it difficult to utilize or gather meaningful information as such. Computational biology techniques have provided us with opportunities to better understand biological systems through refining and organizing large amounts of data into actionable and systematic purviews. The drug repurposing approach has been utilized to overcome the expansive time periods and costs associated with traditional drug development. It deals with discovering new uses of already approved drugs that have an established safety and efficacy profile, thereby, requiring them to go through fewer development phases. Thus, drug repurposing through computational biology provides a systematic approach to drug development and overcomes the constraints of traditional processes. The current chapter covers the basics, approaches and tools of computational biology that can be employed to effectively develop repurposing profile of already approved drug molecules.

PMID:38789189 | DOI:10.1016/bs.pmbts.2024.03.018