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Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 15089

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Special Issue Editors

Prof. Dr. Andrzej Kutner

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Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, The Medical University of Warsaw, 1 Stefana Banacha, 02-097 Warsaw, Poland
Interests: medicinal chemistry; drug discovery; structure-activity relationships; design and synthesis of biologically active compounds; anticancer agents; crystal structure of biomolecules and ligand-receptor interactions, vitamin D analogs, pharmaceutical syntheses
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Geoffrey Brown

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School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Interests: the use of synthetic retinoids and vitamins D as drug substances; cancer and normal stem cells; anticancer therapies; blood cell development; abnormalities in cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Dr. Enikö Kallay

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Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Interests: to understand and unveil biochemical and molecular mechanisms of the anti-tumourigenic effects of vitamin D and dietary calcium for colon cancer prevention; to examine the role of the calcium sensing receptor (CaSR) and of its natural and pharmacologic modulators in colon carcinogenesis and inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The last viral pandemic is now over. There is now a pressing need for the rapid development of effective and safe therapies for widespread diseases and, in particular for aggressive cancers whereby delays to diagnosis and treatment will lead to deaths that were otherwise manageable. In developing new therapies, areas of current interest are the efficacy of drug development-related strategies, entirely new therapeutic molecules, new drug delivery systems, and personalized and digital medicine. There is also the need to integrate various scientific disciplines and industrial activities that focus on these different aspects of drug research.

Volume 1.0 of the Special Issue “Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers” was very successful, with 21 papers. Volume 2.0, dedicated to the Interdisciplinary Conference on Drug Sciences, ACCORD 2022 was equally successful, with 25 papers. Both, Volumes 1.0 and 2.0 were also published as MDPI printed books (https://www.mdpi.com/books/book/5818-novel-strategies-in-the-development-of-new-therapies-drug-substances-and-drug-carriers and https://www.mdpi.com/books/book/7854-novel-strategies-in-the-development-of-new-therapies-drug-substances-and-drug-carriers-2-0).

Due to the continuing interest of authors, we are therefore reopening this topic as volume 3.0 in the International Journal of Molecular Sciences (ISSN 1422-0067, IF 5.6, JCR Category Q1). This third Special Issue aims to promote research in the fields that contribute to conceiving and developing a new drug substance and drug formulation. As with the previous Special Issues, this volume is not limited to any specific aspect of drug development. It aims to cover the entire process of drug development at the molecular level, to conform with the aims and scope of the Journal. Topics include the identification of the molecular target of a new drug, evaluating drug-protein interactions, the modeling, and optimization of functional activity, pre-formulation studies, pharmaceutical carrier development, and preclinical studies.

We would also like to draw your attention to the Interdisciplinary Conference on Drug Sciences, ACCORD 2024, to be held in Warsaw, Poland, 23–25 May 2024 (https://accord.wum.edu.pl/). All the participants of the ACCORD 2024 Conference will have the opportunity to publish a conference paper in this Special Issue. The manuscripts will undergo the regular peer-review process of the Journal.

All interested researchers are invited to submit original papers or review articles related to the topic of this Special Issue, guided by the “Aims and Scope”, “Instructions for Authors”, and the below keywords.

Prof. Dr. Andrzej Kutner
Prof. Dr. Geoffrey Brown
Dr. Enikö Kallay
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

drug design and discovery
antimicrobial drugs, antiviral drugs, antibiotics, cancer prevention and treatment
molecular modeling, molecular mechanisms, crystallography
preclinical studies, pharmacokinetics, pharmacodynamics, pharmacognosy
drug-protein interactions nuclear receptors, receptor agonists and antagonists, stem cells, activity profiling, vaccines, markers, and diagnostics
drug carriers, dosage form, anti-crystal engineering, nanoparticles, dissolution testing

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Published Papers (12 papers)

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12 pages, 1615 KiB

Open AccessArticle

Enhancing Febuxostat Solubility Through Cocrystal Formation: Role of Substrate Selection and Amide Coformers

by Edyta Pindelska, Anita Sarna, Maciej Duszczyk, Anna Zep and Izabela D. Madura

Int. J. Mol. Sci. 2025, 26(7), 3004; https://doi.org/10.3390/ijms26073004 - 26 Mar 2025

Viewed by 216

Abstract

Solubility plays a crucial role in drug bioavailability and therapeutic efficacy. Febuxostat (FEB), a BCS Class II drug used to treat hyperuricemia and gout, has low solubility, limiting its effectiveness. Cocrystallization offers a strategy to enhance solubility without modifying the drug’s chemical structure. While FEB exhibits multiple polymorphic forms, no prior studies have explored cocrystal formation from its commercially available hemihydrate. This study examines whether FEB’s initial form—hemihydrate or anhydrous—affects cocrystal formation. We investigated cocrystals with aromatic amides (nicotinamide, isonicotinamide, and picolinamide) and explored new FEB cocrystals with aliphatic amides (diacetamide, malonamide, and D,L-lactamide) to assess solubility enhancement. Our results show that anhydrous FEB cocrystals reliably form with both aromatic and aliphatic amides, regardless of the starting material. However, the aliphatic coformers lead to thermally unstable cocrystals. Nevertheless, the new cocrystals significantly improved FEB’s solubility, with FEBH-LAC (13.9 mg/L) being the most soluble, but thermally unstable. FEBH-DIA showed the best balance, with 12.2 mg/L solubility and the fastest dissolution rate. These findings highlight cocrystallization with aliphatic amides as a promising approach for enhancing FEB’s solubility and therapeutic potential; however, they may pose problems with stability and reproducibility. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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19 pages, 4680 KiB

Open AccessArticle

Tackling Prostate Cancer with Theranostic E5B9-Bombesin Target Modules (TMs): From Imaging to Treatment with UniCAR T-Cells

by Liliana R. Loureiro, Susan Pike, Melinda Wuest, Cody N. Bergman, Kira R. JØrgensen, Ralf Bergmann, Anja Feldmann, Frank Wuest and Michael Bachmann

Int. J. Mol. Sci. 2025, 26(6), 2686; https://doi.org/10.3390/ijms26062686 - 17 Mar 2025

Viewed by 492

Abstract

Target modules (TMs), intermediate molecules required for UniCAR T-cell therapy, are promising molecules for immunotheranostic approaches. In the current work, we developed TMs containing a monomeric or dimeric form of the antagonist bombesin peptide (BBN2) and assessed their potential for diagnostic imaging using positron emission tomography (PET) as well as immunotherapy in combination with UniCAR T-cells to target and image GRPR expression in prostate cancer. Synthesized monomeric and dimeric BBN2 TMs retained binding to GRPR in vitro. Both BBN2 TMs specifically activated and redirected UniCAR T-cells to eradicate PC3 and LNCaP cancer cells with high efficiency and in a comparable manner. UniCAR T-cells retained a non-exhausted memory phenotype favorable to their persistence and fitness. The ⁶⁸Ga-labeled BBN2 TMs showed proof-of-target towards GRPR in PC3 and LNCaP xenografts with similar uptake profiles for both BBN2 TMs in dynamic PET experiments. Clearance occurred exclusively through renal elimination. A tremendously increased in vivo metabolic stability of the BBN2 TMs was observed compared to their counterparts without E5B9. Both monomeric and dimeric BBN2 TMs represent novel and promising immunotheranostic tools for application in prostate cancer with exceptionally high in vivo metabolic stability. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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17 pages, 23127 KiB

Open AccessArticle

Bicyclic N,S-Acetals Containing Fused Cysteine-Amide System as New Heterocyclic Class Targeting Human Farnesyltransferase (FTase-h)

by Fanny Danton, Mohamed Othman, Ata Martin Lawson, Amaury Farce, Emmanuelle Lipka, Alina Ghinet, Ján Moncol, Abdelhabib Semlali and Adam Daïch

Int. J. Mol. Sci. 2025, 26(4), 1717; https://doi.org/10.3390/ijms26041717 - 17 Feb 2025

Viewed by 554

Abstract

We report in this contribution the synthesis and in vitro biological evaluation of a novel class of chiral thiazoloisoindolinone scaffolds as potent inhibitors against human farnesyltransferase (FTase-h). The targeted products, sulfides (4), sulfoxides (5,6), and sulfones (7), containing up to three points of diversification, were obtained in a short-step sequence starting from the available and cost-effective L-cysteine hydrochloride (1), which is the source of N and S atoms and the chiral pool, and α-carbonyl benzoic acids (2), which are isoindolinone precursors. Concisely, the key ester intermediates (1) provide (a) sulfide-amides (4) by solvent-free amidation, (b) sulfoxides (5,6) by selective S-oxidation using NaIO₄, and (c) sulfones (7) by oxidation using MMPP. Finally, the obtained N,S-acetal systems have shown promising inhibitory activities on FTase-h in the nanomolar range with excellent half maximal inhibitory concentration (IC₅₀) values up to 4.0 nanomolar (for example, 25.1 nM for sulfide 4bI, 67.3 nM for sulfone 7bG, and more interesting of 4.03 nM for sulfoxide 5bG). Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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22 pages, 5740 KiB

Open AccessArticle

Preparation of Diosgenin-Functionalized Gold Nanoparticles: From Synthesis to Antitumor Activities

by Elżbieta U. Stolarczyk, Weronika Strzempek, Magdalena Muszyńska, Marek Kubiszewski, Anna B. Witkowska, Kinga Trzcińska, Piotr Wojdasiewicz and Krzysztof Stolarczyk

Int. J. Mol. Sci. 2025, 26(3), 1088; https://doi.org/10.3390/ijms26031088 - 27 Jan 2025

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Abstract

Cancer ranks among the top causes of illness and death globally. Nanotechnology holds considerable promise for enhancing the effectiveness of therapeutic and diagnostic approaches in cancer treatment. Our study presents a promising strategy for applying thiocompound nanomedicine in cancer therapy. Our first study aimed to investigate the biological properties of a new compound thiodiosgenin (TDG)—a new derivative of diosgenin—a natural compound with known antioxidant and anticancer properties. Our current second study aimed to compare the therapeutic efficacy of a new diosgenin—functionalized gold nanoparticles—with its precursor on prostate cancer (DU-145) cell lines. Moreover, the safety of the new thio-derivative and new conjugates was tested against the human epithelial line PNT-2. New advanced analytical techniques were developed for the characterization of nanomaterials using methods such as SP-ICP-MS, UV-Vis, TEM, NMR, FT-IR ELS, and TGA. Our synthetic approach was based, on the one hand, on the ligand exchange of citrates to thiodiosgenin (TDG) on gold nanoparticles, and on the other hand, on the attachment of DG through an ester bond to the linker, which was 3-mercaptopropionic acid (MPA) on gold nanoparticles. Initial in vitro studies indicate that TDG shows greater cytotoxic effects on cancer cells but poses risks to normal prostate epithelial cells (PNT-2). It was demonstrated that all the conjugates produced exhibited significant cytotoxic effects against cancer cells while being less harmful to normal prostate epithelial cells (PNT-2) compared to TDG itself. All the obtained conjugates showed antitumor properties; however, for targeted transport, the system referred to as AuNPs-MPAm1-DG is promising, due to the size of the nanoparticles of 53 nm, zeta potential of -30 mV, and loading content of 27.6%. New methods for synthesizing conjugates with diosgenin were developed and optimized for medical applications. Advanced new analytical methodologies were developed to characterize new conjugates, particularly the use of SP-ICP-MS, to solve existing differences in the shape and morphology of the surface of new conjugates. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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15 pages, 2179 KiB

Open AccessArticle

Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists

by Jonathan Hoffmann, Dirk Schepmann, Constantin Daniliuc, Marcel Bermudez and Bernhard Wünsch

Int. J. Mol. Sci. 2025, 26(3), 998; https://doi.org/10.3390/ijms26030998 - 24 Jan 2025

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Abstract

The hydroxylated perhydroquinoxaline 14 was designed by conformational restriction of the prototypical κ receptor agonist U-50,488 and the introduction of an additional polar group. The synthesis of 14 comprised ten reaction steps starting from diethyl 3-hydroxyglutarate (4). The first key step was the diastereoselective establishment of the tetrasubstituted cyclohexane 7 by the reaction of dialdehyde 6 with benzylamine and nitromethane. The piperazine ring was annulated by the reaction of silyloxy-substituted cyclohexanetriamine 8 with dimethyl oxalate. The pharmacophoric structural elements characteristic for κ receptor agonists were finally introduced by functional group modifications. The structure including the relative configuration of the tetrasubstituted cyclohexane derivative (2r,5s)-7a and the perhydroquinoxaline 9 was determined unequivocally by X-ray crystal structure analysis. The hydroxylated perhydroquinoxaline 14 showed moderate κ receptor affinity (K_i = 599 nM) and high selectivity over μ, δ, σ₁, and σ₂ receptors. An ionic interaction between the protonated pyrrolidine of 14 and D138 of κ receptor anchors 14 in the κ receptor binding pocket. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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25 pages, 3839 KiB

Open AccessArticle

Optimizing Therapeutics for Intratumoral Cancer Treatments: Antiproliferative Vanadium Complexes in Glioblastoma

by Andrew C. Bates, Kameron L. Klugh, Anna O. Galaeva, Raley A. Patch, John F. Manganaro, Skyler A. Markham, Emma Scurek, Aviva Levina, Peter A. Lay and Debbie C. Crans

Int. J. Mol. Sci. 2025, 26(3), 994; https://doi.org/10.3390/ijms26030994 - 24 Jan 2025

Cited by 2 | Viewed by 1143

Abstract

Glioblastoma, an aggressive cancer, is difficult to treat due to its location, late detection, drug resistance, and poor absorption of chemotherapeutics. Intratumoral drug administration offers a promising potential treatment alternative with localized delivery and minimal systemic toxicity. Vanadium(V) coordination complexes, incorporating Schiff base and catecholate ligands, have shown effects as antiproliferative agents with tunable efficacy and reactivity, stability, steric bulk, hydrophobicity, uptake, and toxicity optimized for the intratumoral administration vehicle. A new series of oxovanadium(V) Schiff base–catecholate complexes were synthesized and characterized using nuclear magnetic resonance (NMR), UV-Vis, and infrared spectroscopy and mass spectrometry. Stability under physiological conditions was assessed via UV-Vis spectroscopy, and the antiproliferative activity was evaluated in T98G glioblastoma and SVG p12 normal glial cells using viability assays. The newly synthesized [VO(3-tBuHSHED)(TIPCAT)] complex was more stable (t_1/2 ~4.5 h) and had strong antiproliferative activity (IC₅₀ ~1.5 µM), comparing favorably with the current lead compound, [VO(HSHED)(DTB)]. The structural modifications enhanced stability, hydrophobicity, and steric bulk through substitution with iso-propyl and tert-butyl groups. The improved properties were attributed to steric hindrance associated with the new Schiff base and catecholato ligands, as well as the formation of non-toxic byproducts upon degradation. The [VO(3-tBuHSHED)(TIPCAT)] complex emerges as a promising candidate for glioblastoma therapy by demonstrating enhanced stability and a greater selectivity, which highlights the role of strategic ligand design in developing localized therapies for the treatment of resistant cancers. In reporting the new class of compounds effective against T98G glioblastoma cells, we describe the generally desirable properties that potential drugs being developed for intratumoral administration should have. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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18 pages, 1886 KiB

Open AccessArticle

Design and Synthesis of Potential Multi-Target Antidepressants: Exploration of 1-(4-(7-Azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione Derivatives with Affinity for the Serotonin Transporter

by Martyna Z. Wróbel, Andrzej Chodkowski, Agata Siwek, Grzegorz Satała, Andrzej J. Bojarski and Maciej Dawidowski

Int. J. Mol. Sci. 2024, 25(20), 11276; https://doi.org/10.3390/ijms252011276 - 20 Oct 2024

Cited by 1 | Viewed by 1375

Abstract

We describe the design, synthesis and structure–activity relationship of a novel series of 1-(4-(7-azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT_1A) and dopamine (D₂) receptors and the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters as multi-target directed ligands for the treatment of depression. All of the tested compounds demonstrated good affinity for the serotonin transporter (SERT). Among them, compounds 11 and 4 emerged as the lead candidates because of their promising pharmacological profile based on in vitro studies. Compound 11 displayed a high affinity for the 5-HT_1A (K_i = 128.0 nM) and D₂ (K_i = 51.0 nM) receptors, and the SERT (K_i = 9.2 nM) and DAT (K_i = 288.0 nM) transporters, whereas compound 4 exhibited the most desirable binding profile to SERT/NET/DAT among the series: K_i = 47.0 nM/167.0 nM/43% inhibition at 1 µM. These results suggest that compounds 4 and 11 represent templates for the future development of multi-target antidepressant drugs. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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17 pages, 1746 KiB

Open AccessArticle

Assessment of Dried Serum Spots (DSS) and Volumetric-Absorptive Microsampling (VAMS) Techniques in Therapeutic Drug Monitoring of (Val)Ganciclovir—Comparative Study in Analytical and Clinical Practice

by Arkadiusz Kocur, Agnieszka Czajkowska, Mateusz Moczulski, Bartłomiej Kot, Jacek Rubik and Tomasz Pawiński

Int. J. Mol. Sci. 2024, 25(16), 8760; https://doi.org/10.3390/ijms25168760 - 12 Aug 2024

Cited by 2 | Viewed by 1238

Abstract

Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are antiviral medications primarily used to treat infections caused by cytomegalovirus (CMV), particularly in immunocompromised individuals such as solid organ transplant (SOT) recipients. Therapy with GCV is associated with significant side effects, including bone marrow suppression. Therefore, therapeutic drug monitoring (TDM) is mandatory for an appropriate balance between subtherapeutic and toxic drug levels. This study aimed to develop and validate three novel methods based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for GCV determination in serum (reference methodology), dried serum spots (DSS), and VAMS-Mitra™ devices. The methods were optimized and validated in the 0.1–25 mg/L calibration range. The obtained results fulfilled the EMA acceptance criteria for bioanalytical method validation. Assessment of DSS and VAMS techniques extended GCV stability to serum for up to a minimum of 49 days (at room temperature, with desiccant). Developed methods were effectively evaluated using 80 clinical serum samples from pediatric renal transplant recipients. Obtained samples were used for DSS, and dried serum VAMS samples were manually generated in the laboratory. The results of GCV determination using serum-, DSS- and VAMS-LC-MS/MS methods were compared using regression analysis and bias evaluation. The conducted statistical analysis confirmed the interchangeability between developed assays. The DSS and VAMS samples are more accessible and stable during storage, transport and shipment than classic serum samples. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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Review

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19 pages, 1743 KiB

Open AccessReview

Therapeutic Drug Monitoring of Low Methotrexate Doses for Drug Exposure and Adherence Assessment—Pre-Analytical Variables, Bioanalytical Issues, and Current Clinical Applications

by Arkadiusz Kocur, Aleksandra Mikulska, Mateusz Moczulski and Tomasz Pawiński

Int. J. Mol. Sci. 2024, 25(24), 13430; https://doi.org/10.3390/ijms252413430 - 14 Dec 2024

Viewed by 1495

Abstract

Methotrexate (MTX) is an antifolic agent used in the first line of anti-inflammatory disease treatment and some oncologic issues. The metabolism of MTX is rapid, and the MTX concentration in the blood is not significant 24 h after administration. Unlike this, methotrexate polyglutamates (MTXPGs) can be informative biomarkers of drug exposure. It is widely concluded that MTXPG retention in red blood cells (RBCs) is related to appropriate efficacy, drug exposure, and toxicity during treatment. Therefore, the mentioned biomarker may be appropriately used for the PK/PD monitoring of low-dose MTX (LDMTX) treatment. The presented review study aimed to review published studies about MTX determination in clinical practice, including pre-analytical variability, bioanalytical considerations, and clinical applications of the methods for pharmacotherapy supporting target populations. In total, 14 papers from the field of bioanalytics have been included in the main review. For each phase of an analytical process, the best practises and main findings were defined as guidelines for proper analytical method optimisation, validation, and standard operation procedure implementation in clinical practice. The presented study is the first comprehensive review of MTX and its methods of metabolite determination to account for pre-analytical, analytical, and post-analytical phases concerning the TDM process. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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21 pages, 1224 KiB

Open AccessReview

Towards Targeting Endothelial Rap1B to Overcome Vascular Immunosuppression in Cancer

by Behshid Ghadrdoost Nakhchi, Ramoji Kosuru and Magdalena Chrzanowska

Int. J. Mol. Sci. 2024, 25(18), 9853; https://doi.org/10.3390/ijms25189853 - 12 Sep 2024

Cited by 1 | Viewed by 1906

Abstract

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression—a state where ECs resist cytotoxic CD8⁺ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8⁺ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A’s immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies’ efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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21 pages, 4223 KiB

Open AccessReview

Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ

by Katarzyna Powała, Teresa Żołek, Geoffrey Brown and Andrzej Kutner

Int. J. Mol. Sci. 2024, 25(12), 6568; https://doi.org/10.3390/ijms25126568 - 14 Jun 2024

Cited by 2 | Viewed by 2108

Abstract

All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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8 pages, 581 KiB

Open AccessCase Report

Pseudohyperaldosteronism Due to Licorice: A Practice-Based Learning from a Case Series

by Chiara Sabbadin, Andrea Graziani, Alessandro Bavaresco, Pierluigi Mazzeo, Irene Tizianel, Filippo Ceccato, Decio Armanini and Mattia Barbot

Int. J. Mol. Sci. 2024, 25(13), 7454; https://doi.org/10.3390/ijms25137454 - 7 Jul 2024

Cited by 3 | Viewed by 1690

Abstract

Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels. It can be caused by several causes, but the most frequent is due to excess intake of licorice. The effect is mediated by the active metabolite of licorice, glycyrrhetinic acid (GA), which acts by blocking the 11-hydroxysteroid dehydrogenase type 2 and binding to the mineralocorticoid receptor (MR) as an agonist. The management of licorice-induced PHA depends on several individual factors, such as age, gender, comorbidities, duration and amount of licorice intake, and metabolism. The clinical picture usually reverts upon licorice withdrawal, but sometimes mineralocorticoid-like effects can be critical and persist for several weeks, requiring treatment with MR blockers and potassium supplements. Through this case series of licorice-induced PHA, we aim to increase awareness about exogenous PHA, and the possible risk associated with excess intake of licorice. An accurate history is mandatory in patients with hypertension and hypokalemia to avoid unnecessary testing. GA is a component of several products, such as candies, breath fresheners, beverages, tobacco, cosmetics, and laxatives. In recent years, the mechanisms of action of licorice and its active compounds have been better elucidated, suggesting its benefits in several clinical settings. Nevertheless, licorice should still be consumed with caution, considering that licorice-induced PHA is still an underestimated condition, and its intake should be avoided in patients with increased risk of licorice toxicity due to concomitant comorbidities or interfering drugs. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)

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