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Targeting Cellular Key Points in Drug Discovery

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A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (20 July 2023) | Viewed by 5262

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Special Issue Editors

Dr. Jessica Ceramella

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Guest Editor

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
Interests: anticancer drugs; medicinal chemistry; nutraceuticals; multi-target agents; bioactive products; natural extracts; antioxidants; cancer
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Domenico Iacopetta

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Guest Editor

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, 87036 Arcavacata di Rende, Italy
Interests: food; medicinal chemistry; bioactive products; nutraceuticals; phytochemicals; natural products extraction and isolation; antioxidants; anti-inflammatory; antimicrobials enzyme inhibition; cancer; cell biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

You are invited to contribute to this Special Issue entitled “Targeting Cellular Key Points in Drug Discovery”. It is well known that unhealthy lifestyles contribute worldwide to increasing the risk of non-communicable diseases. Indeed, despite the numerous efforts of the research, the incidence of infectious, cardiovascular, inflammatory, neurodegenerative and cancer diseases are constantly growing. The current drugs used in therapies suffer some limitations, such as their numerous side effects due to the low specificity, their non-optimal pharmacokinetic profiles, as well as the onset of resistance phenomena.

Considering this scenario, the development of new synthetic and natural molecules with improved pharmaceutical and pharmacokinetic profiles, as well as with the ability to interfere with specific targets involved in the development and progression of the main non-communicable diseases, is urgently needed.

Thus, this Special Issue addresses original research papers or review articles on these important topics, highlighting the importance of some library of compounds or natural extracts able to interfere with significant targets of pharmaceutical interest.

Dr. Jessica Ceramella
Dr. Domenico Iacopetta
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. Applied Sciences is an international peer-reviewed open access semimonthly 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 2400 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

targeted therapy
non-communicable diseases
enzymes
synthetic compounds
natural extracts
molecular modeling
chemically modified drugs

Published Papers (4 papers)

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Research

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19 pages, 4841 KiB

Open AccessArticle

Comparative Study of the Anticancer Effects of Selenium Nanoparticles and Selenium Nanorods: Regulation of Ca²⁺ Signaling, ER Stress and Apoptosis

by Elena G. Varlamova, Ilya V. Baimler, Sergey V. Gudkov and Egor A. Turovsky

Appl. Sci. 2023, 13(19), 10763; https://0-doi-org.brum.beds.ac.uk/10.3390/app131910763 - 27 Sep 2023

Viewed by 752

Abstract

The anti-cancer effects of selenium sources are well known. Among other things, selenium has been shown to have a pleiotropic effect, causing cancer cell death without affecting the healthy cell’s viability, or, in the case of brain cells, has a cytoprotective effect. This feature of selenium determined its use in medicine and its use as part of dietary supplements. In recent years, selenium in the form of nanoparticles has received increased attention. Selenium nanoparticles also have anti-cancer effects, and their use appears to be more effective at significantly lower doses compared to other sources of selenium. The shape and size of nanoparticles largely affect the efficiency of nanoselenium application. We obtained two different types of selenium nanoparticles via the laser ablation technique—spherical selenium nanoparticles (SeNPs) about 100 nm in diameter and grown selenium nanorods (SeNrs) about 1 μm long and about 100 nm thick. We compared the anti-cancer efficacy of these two types of selenium nanoparticles using inhibitory analysis, PCR analysis and fluorescence microscopy. It turned out that both types of nanoparticles with high efficiency dose-dependently activate apoptosis in the human glioblastoma cell line A-172, as the most aggressive type of brain tumor. Apoptosis induction was determined not only by the concentration of nanoparticles, but also by the time. It was shown that SeNrs induce the process of apoptosis in glioblastoma cells more efficiently during 24 h of exposure and their effect is enhanced after 48 h without activation of necrosis, whereas the use of spherical SeNPs after 48 h of exposure can cause necrosis in some glioblastoma cells. It has been shown that Ca²⁺ signals of glioblastoma cells are significantly different for SeNPs and SeNrs. SeNPs cause a dose-dependent transient increase in the number of Ca²⁺ ions in the cell cytosol ([Ca²⁺]_i), while SeNrs cause a slow rise in [Ca²⁺]_i reaching a new stationary level, which may determine the cytotoxic effects of nanoparticles. It turned out that SeNPs and SeNrs cause depletion of the Ca²⁺ depot of the endoplasmic reticulum and ER-stress, which correlates with increased expression of genes encoding proapoptotic proteins. In our study, it was found that SeNPs do not activate the Ca²⁺ signaling system of healthy L-929 mouse fibroblast cells, while SeNrs activate a moderate slow growth in [Ca²⁺]_i. That fact could indicate a lower selectivity of the SeNrs action. Full article

(This article belongs to the Special Issue Targeting Cellular Key Points in Drug Discovery)

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16 pages, 4060 KiB

Open AccessArticle

A Resveratrol Phenylacetamide Derivative Perturbs the Cytoskeleton Dynamics Interfering with the Migration Potential in Breast Cancer

by Jessica Ceramella, Adele Chimento, Domenico Iacopetta, Arianna De Luca, Gabriela Coronel Vargas, Camillo Rosano, Vincenzo Pezzi, Carmela Saturnino and Maria Stefania Sinicropi

Appl. Sci. 2022, 12(13), 6531; https://0-doi-org.brum.beds.ac.uk/10.3390/app12136531 - 28 Jun 2022

Cited by 1 | Viewed by 1139

Abstract

Chemotherapy is commonly used for cancer treatment, however the lack of selectivity on healthy cells and the development of resistance phenomena are the major issues. A better understanding of cancer genetics helped the development of new targeted anticancer treatments, which permit drug delivery with high specificity and lower toxicity. Moreover, the multi-target drug design concept represents the current trend for future drug research and development. Starting from good results previously obtained by our research group on the resveratrol (RSV) phenylacetamide derivative 2, which displayed an interesting anti-inflammatory and anti-proliferative activity towards the breast cancer cells MCF-7 and MDA-MB-231, we identified other features, as the ability to perturb the cytoskeleton dynamics and interfere with the migration and metastatic processes. In vitro and in silico studies demonstrate that the derivative 2 is a tubulin and actin polymerization inhibitor and an actin depolymerization promotor. In addition, it interferes with the metastatic potential in both the breast cancer cells, inhibiting the in vitro cell migration and decreasing the spheroids number. These promising results demonstrate that the RSV phenylacetamide derivative 2 could be an important starting point in the discovery and development of safer and more efficacy multi-targeted agents. Full article

(This article belongs to the Special Issue Targeting Cellular Key Points in Drug Discovery)

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27 pages, 3030 KiB

Open AccessArticle

Targeting TGF-ß in the Central Nervous System: Assessment of Cynomolgus Monkey—Toxicity and Pharmacokinetics for an LNA-Antisense Oligonucleotide

by Sebastian Peters, Eva Wirkert, Sabrina Kuespert, Rosmarie Heydn, Sven Korte, Lars Mecklenburg, Ludwig Aigner, Siw Johannesen, Tim-Henrik Bruun and Ulrich Bogdahn

Appl. Sci. 2022, 12(3), 973; https://0-doi-org.brum.beds.ac.uk/10.3390/app12030973 - 18 Jan 2022

Viewed by 1613

Abstract

Increasingly antisense oligonucleotides (ASOs) are developed for potential treatment of CNS disorders, and due to the inability to cross the blood brain barrier, they require direct administration into the cerebrospinal fluid (CSF). In this regard, intrathecal (i.th.) administration in cynomolgus monkeys (Macaca fascicularis) is a well-established approach for preclinical safety studies. Here, we present an innovative preclinical approach that is intended to support rapid entry into clinical development with ASOs targeting the CNS. The preclinical approach comprises one non-GLP study in 26 non-human primates, followed by a pivotal GLP repeated dose toxicity study in the same species. No pivotal rodent studies were conducted, and regulatory guidance to initiate this study was met by in vitro work. The non-GLP study consists of three separate phases: Phase A determines toxicity after i.th. administrations with five escalating dose levels in a single male and female animal, respectively. Dosing is conducted on days 1, 8, 15, 22, and 29 and the experiment is terminated 36 days after start of the study. The second phase (Phase B) investigates pharmacokinetics over a 2- or 4-week period at two dose levels following single administrations in eight (8) animals (4 females, 4 males). Finally, a third phase (Phase C) investigates toxicity and pharmacokinetics after repeated (9×) dosing over a 13-week period at two dose levels in sixteen (8 females, 8 males) animals. In each phase, clinical observations and physical/neurological parameters are investigated directly pre-dose, 4 h and 24 h post-dose, respectively. In all phases, CSF and blood samples are taken pre-dose and after each dosing, for determination of test article concentration, biomarkers of tolerability and biomarkers of pharmacology. In all phases, tissue samples from the liver, kidney, spinal cord, and brain are collected for determination of NVP-13 tissue concentrations. The above concept has successfully supported first-in-human clinical trials. The entire non-GLP program is completed within less than six months and requires fewer animals in comparison to the conduct of three independent studies. Full article

(This article belongs to the Special Issue Targeting Cellular Key Points in Drug Discovery)

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Review

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16 pages, 495 KiB

Open AccessReview

Immuno-PET for Glioma Imaging: An Update

by Maria Silvia De Feo, Giorgia Maria Granese, Miriam Conte, Barbara Palumbo, Stefano Panareo, Viviana Frantellizzi, Giuseppe De Vincentis and Luca Filippi

Appl. Sci. 2024, 14(4), 1391; https://0-doi-org.brum.beds.ac.uk/10.3390/app14041391 - 08 Feb 2024

Viewed by 740

Abstract

Despite significant advances in glioma diagnosis and treatment, overall outcomes remain suboptimal. Exploring novel therapeutic avenues show promise in advancing the field. Theranostics, an evolving discipline integrating diagnosis and therapy, emerges as a particularly auspicious approach. However, an unmet need exists for glioma-associated biomarkers as theranostic targets. Immuno-positron emission tomography (Immuno-PET), a pioneering method uniting PET diagnostic precision with antibody specificity, holds potential for identifying cancer-associated biomarkers. This review aims to provide an updated overview of immuno-PET applications in gliomas. Notably, [⁴⁴Sc]-CHX-A″-DTPA-Cetuximab-Fab targeting Epidermal Growth Factor Receptor (EGFR) has displayed promise in glioma xenografts, enabling potential imaging at 4 h post-injection. Similarly, [⁸⁹Zr]-bevacizumab targeting vascular endothelial growth factor (VEGF) yielded encouraging results in preclinical models and a pioneering clinical trial for pediatric patients with diffuse intrinsic pontine glioma (DIPG). Several cell differentiation markers, including CD146, indicative of tumor aggressiveness, and CD11b, reflecting tumor-associated myeloid cells (TAMCs), proved effective targets for immuno-PET. Additionally, immuno-PET directed at prostate-specific antigen (PSMA) demonstrated efficacy in imaging glioma-associated neovasculature. While holding promise for precise diagnosis and treatment guidance, challenges persist in achieving target specificity and selecting suitable radionuclides. Further studies are imperative to advance the field and bridge a translational gap from bench to bedside. Full article

(This article belongs to the Special Issue Targeting Cellular Key Points in Drug Discovery)

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