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Biomedicines
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Recent Advances in Drug Repositioning
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Recent Advances in Drug Repositioning

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 7068

Special Issue Editors

Dr. Jay Trivedi

E-Mail Website
Guest Editor
Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, USA
Interests: virology; biotechnology stem cell biology; drug discovery; anti-viral therapeutics; tissue regeneration
Dr. Ákos Jerzsele

E-Mail Website
Guest Editor
1. Department of Pharmacology and Toxicology, University of Veterinary Medicine, István utca 2, H-1078 Budapest, Hungary
2. National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, University of Veterinary Medicine, István utca 2, H-1078 Budapest, Hungary
Interests: pharmacology; drug repositioning; pharmacokinetics; antimicrobial resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viral infections such as influenza, HIV, hepatitis, Ebola, Dengue, and SARS-CoV have claimed millions of human lives over time. The emergence and reemergence of new viruses have raised significant concerns. Their complex multistep lifecycles allow viruses to evade the host immune response, proliferate within the host, and produce infectious progeny virions. Furthermore, with the rapid replication rate and minimal proofreading activity during replication, viruses develop mutations that enable them to develop swift resistance to therapeutic drugs. Hence, there remains a persistent need to discover novel, more efficient broad-spectrum antiviral therapeutic strategies.

The development and characterization of novel antiviral molecules from the beginning costs an average of USD 400 million to USD 2 billion per drug. The journey from the laboratory to the clinic expends more than a decade. Despite consuming extensive resources, the success rate of novel drugs is meager. The utilization of drug repurposing/recycling approaches has generated substantial interest in overcoming these drawbacks. A drastic reduction in the failure rate, which is otherwise >90%, is achieved with the drug repurposing approach. The recent exploration of the drug repurposing approach to combat the COVID-19 pandemic has further validated that reinvestigating the in-practice drugs for a new application is more beneficial than designing novel drugs.

The first successful example of drug repurposing is zidovudine (AZT), developed as an anti-cancer agent in the 1960s and later approved by the US FDA as an anti-HIV therapeutic drug in the late 1980s after fast-track clinical trials. Since then, this approach has been successfully utilized to develop effective therapeutic strategies not only against viral diseases but also against many pathological conditions, including cancer and neurodegenerative diseases.

For this Special Issue, we welcome all perspectives and high-quality research articles, including but not limited to original research articles and review articles.

Dr. Jay Trivedi
Dr. Ákos Jerzsele
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • viruses
  • host immune response
  • drug resistance
  • antiviral molecules
  • drug repurposing

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Published Papers (4 papers)

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Research

16 pages, 1865 KiB  
Article
Antiviral Drug Candidate Repositioning for Streptococcus suis Infection in Non-Tumorigenic Cell Models
by Ashley Anzet van Niekerk, Sara Maluck, Patrik Mag, Csaba Kővágó, Ádám Kerek, Ákos Jerzsele, Torsten Steinmetzer and Erzsébet Pászti-Gere
Biomedicines 2024, 12(4), 783; https://doi.org/10.3390/biomedicines12040783 - 2 Apr 2024
Viewed by 1242
Abstract
The increasing prevalence of antimicrobial resistance against zoonotic bacteria, including Streptococcus (S.) suis, highlights the need for new therapeutical strategies, including the repositioning of drugs. In this study, susceptibilities of bacterial isolates were tested toward ten different 3-amidinophenyalanine (Phe(3-Am)) derivatives via determination [...] Read more.
The increasing prevalence of antimicrobial resistance against zoonotic bacteria, including Streptococcus (S.) suis, highlights the need for new therapeutical strategies, including the repositioning of drugs. In this study, susceptibilities of bacterial isolates were tested toward ten different 3-amidinophenyalanine (Phe(3-Am)) derivatives via determination of minimum inhibitory concentration (MIC) values. Some of these protease inhibitors, like compounds MI-432, MI-471, and MI-476, showed excellent antibacterial effects against S. suis. Their drug interaction potential was investigated using human liver microsomal cytochrome P450 (CYP450) measurements. In our work, non-tumorigenic IPEC-J2 cells and primary porcine hepatocytes were infected with S. suis, and the putative beneficial impact of these inhibitors was investigated on cell viability (Neutral red assay), on interleukin (IL)-6 levels (ELISA technique), and on redox balance (Amplex red method). The antibacterial inhibitors prevented S. suis-induced cell death (except MI-432) and decreased proinflammatory IL-6 levels. It was also found that MI-432 and MI-476 had antioxidant effects in an intestinal cell model upon S. suis infection. Concentration-dependent suppression of CYP3A4 function was found via application of all three inhibitors. In conclusion, our study suggests that the potential antiviral Phe(3-Am) derivatives with 2′,4′ dichloro-biphenyl moieties can be considered as effective drug candidates against S. suis infection due to their antibacterial effects. Full article
(This article belongs to the Special Issue Recent Advances in Drug Repositioning)
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20 pages, 4435 KiB  
Article
The Anti-Virulence Activities of the Antihypertensive Drug Propranolol in Light of Its Anti-Quorum Sensing Effects against Pseudomonas aeruginosa and Serratia marcescens
by Hadil Faris Alotaibi, Haifa Alotaibi, Khaled M. Darwish, El-Sayed Khafagy, Amr S. Abu Lila, Mohamed A. M. Ali, Wael A. H. Hegazy and Samar Zuhair Alshawwa
Biomedicines 2023, 11(12), 3161; https://doi.org/10.3390/biomedicines11123161 - 28 Nov 2023
Cited by 10 | Viewed by 1983
Abstract
The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting [...] Read more.
The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the β-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol’s effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies. Full article
(This article belongs to the Special Issue Recent Advances in Drug Repositioning)
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14 pages, 3021 KiB  
Article
Azadiradione, a Component of Neem Oil, Behaves as a Superoxide Dismutase Mimic When Scavenging the Superoxide Radical, as Shown Using DFT and Hydrodynamic Voltammetry
by Raiyan Sakib, Francesco Caruso, Stuart Belli and Miriam Rossi
Biomedicines 2023, 11(11), 3091; https://doi.org/10.3390/biomedicines11113091 - 18 Nov 2023
Cited by 2 | Viewed by 1706
Abstract
The neem tree, Azadirachta indica, belongs to the Meliaceae family, and its use in the treatment of medical disorders from ancient times to the present in the traditional medical practices of Asia, Africa and the Middle East is well-documented. Neem oil, extracted [...] Read more.
The neem tree, Azadirachta indica, belongs to the Meliaceae family, and its use in the treatment of medical disorders from ancient times to the present in the traditional medical practices of Asia, Africa and the Middle East is well-documented. Neem oil, extracted from the seeds of the fruit, is widely used, with promising medicinal benefits. Azadiradione, a principal antioxidant component of the seeds of A. indica, is known to reduce oxidative stress and has anti-inflammatory effects. To directly measure the antioxidant ability of neem oil, we used Rotating Ring Disk Electrode (RRDE) hydrodynamic voltammetry to quantify how it can scavenge superoxide radical anions. The results of these experiments show that neem oil is approximately 26 times stronger than other natural products, such as olive oil, propolis and black seed oil, which were previously measured using this method. Next, computational Density Functional Theory (DFT) methods were used to arrive at a mechanism for the scavenging of superoxide radical anions with azadiradione. Our work indicates that azadiradione is an effective antioxidant and, according to our DFT study, its scavenging of the superoxide radical anion occurs through a reaction mechanism in which azadiradione mimics the antioxidant action of superoxide dismutase (SOD). In this mechanism, analogous to the SOD enzymatic reaction, azadiradione is regenerated, along with the production of two products: hydrogen peroxide and molecular oxygen. This antioxidant process provides an explanation for azadiradione’s more general and protective biochemical effects. Full article
(This article belongs to the Special Issue Recent Advances in Drug Repositioning)
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17 pages, 599 KiB  
Article
Predicting Drug–Gene–Disease Associations by Tensor Decomposition for Network-Based Computational Drug Repositioning
by Yoonbee Kim and Young-Rae Cho
Biomedicines 2023, 11(7), 1998; https://doi.org/10.3390/biomedicines11071998 - 14 Jul 2023
Cited by 3 | Viewed by 1688
Abstract
Drug repositioning offers the significant advantage of greatly reducing the cost and time of drug discovery by identifying new therapeutic indications for existing drugs. In particular, computational approaches using networks in drug repositioning have attracted attention for inferring potential associations between drugs and [...] Read more.
Drug repositioning offers the significant advantage of greatly reducing the cost and time of drug discovery by identifying new therapeutic indications for existing drugs. In particular, computational approaches using networks in drug repositioning have attracted attention for inferring potential associations between drugs and diseases efficiently based on the network connectivity. In this article, we proposed a network-based drug repositioning method to construct a drug–gene–disease tensor by integrating drug–disease, drug–gene, and disease–gene associations and predict drug–gene–disease triple associations through tensor decomposition. The proposed method, which ensembles generalized tensor decomposition (GTD) and multi-layer perceptron (MLP), models drug–gene–disease associations through GTD and learns the features of drugs, genes, and diseases through MLP, providing more flexibility and non-linearity than conventional tensor decomposition. We experimented with drug–gene–disease association prediction using two distinct networks created by chemical structures and ATC codes as drug features. Moreover, we leveraged drug, gene, and disease latent vectors obtained from the predicted triple associations to predict drug–disease, drug–gene, and disease–gene pairwise associations. Our experimental results revealed that the proposed ensemble method was superior for triple association prediction. The ensemble model achieved an AUC of 0.96 in predicting triple associations for new drugs, resulting in an approximately 7% improvement over the performance of existing models. It also showed competitive accuracy for pairwise association prediction compared with previous methods. This study demonstrated that incorporating genetic information leads to notable advancements in drug repositioning. Full article
(This article belongs to the Special Issue Recent Advances in Drug Repositioning)
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