A Computational Framework to Identify Biomarkers for Glioma Recurrence and Potential Drugs Targeting Them

Background: Recurrence is still a major obstacle to the successful treatment of gliomas. Understanding the underlying mechanisms of recurrence may help for developing new drugs to combat gliomas recurrence. This study provides a strategy to discover new drugs for recurrent gliomas based on drug perturbation induced gene expression changes.Methods: The RNA-seq data of 511 low grade gliomas primary tumor samples (LGG-P), 18 low grade gliomas recurrent tumor samples (LGG-R), 155 glioblastoma multiforme primary tumor samples (GBM-P), and 13 glioblastoma multiforme recurrent tumor samples (GBM-R) were downloaded from TCGA database. DESeq2, key driver analysis and weighted gene correlation network analysis (WGCNA) were conducted to identify differentially expressed genes (DEGs), key driver genes and coexpression networks between LGG-P vs LGG-R, GBM-P vs GBM-R pairs. Then, the CREEDS database was used to find potential drugs that could reverse the DEGs and key drivers.Results: We identified 75 upregulated and 130 downregulated genes between LGG-P and LGG-R samples, which were mainly enriched in human papillomavirus (HPV) infection, PI3K-Akt signaling pathway, Wnt signaling pathway, and ECM-receptor interaction. A total of 262 key driver genes were obtained with frizzled class receptor 8 (FZD8), guanine nucleotide-binding protein subunit gamma-12 (GNG12), and G protein subunit β2 (GNB2) as the top hub genes. By screening the CREEDS database, we got 4 drugs (Paclitaxel, 6-benzyladenine, Erlotinib, Cidofovir) that could downregulate the expression of up-regulated genes and 5 drugs (Fenofibrate, Oxaliplatin, Bilirubin, Nutlins, Valproic acid) that could upregulate the expression of down-regulated genes. These drugs may have a potential in combating recurrence of gliomas.Conclusion: We proposed a time-saving strategy based on drug perturbation induced gene expression changes to find new drugs that may have a potential to treat recurrent gliomas.

Small Drugs, Huge Impact: The Extraordinary Impact of Antisense Oligonucleotides in Research and Drug Development

Antisense oligonucleotides (ASOs) are an increasingly represented class of drugs. These small sequences of nucleotides are designed to precisely target other oligonucleotides, usually RNA species, and are modified to protect them from degradation by nucleases. Their specificity is due to their sequence, so it is possible to target any RNA sequence that is already known. These molecules are very versatile and adaptable given that their sequence and chemistry can be custom manufactured. Based on the chemistry being used, their activity may significantly change and their effects on cell function and phenotypes can differ dramatically. While some will cause the target RNA to decay, others will only bind to the target and act as a steric blocker. Their incredible versatility is the key to manipulating several aspects of nucleic acid function as well as their process, and alter the transcriptome profile of a specific cell type or tissue. For example, they can be used to modify splicing or mask specific sites on a target. The entire design rather than just the sequence is essential to ensuring the specificity of the ASO to its target. Thus, it is vitally important to ensure that the complete process of drug design and testing is taken into account. ASOs’ adaptability is a considerable advantage, and over the past decades has allowed multiple new drugs to be approved. This, in turn, has had a significant and positive impact on patient lives. Given current challenges presented by the COVID-19 pandemic, it is necessary to find new therapeutic strategies that would complement the vaccination efforts being used across the globe. ASOs may be a very powerful tool that can be used to target the virus RNA and provide a therapeutic paradigm. The proof of the efficacy of ASOs as an anti-viral agent is long-standing, yet no molecule currently has FDA approval. The emergence and widespread use of RNA vaccines during this health crisis might provide an ideal opportunity to develop the first anti-viral ASOs on the market. In this review, we describe the story of ASOs, the different characteristics of their chemistry, and how their characteristics translate into research and as a clinical tool.

Targeting of Regulators as a Promising Approach in the Search for Novel Antimicrobial Agents

Since the discovery of penicillin in the first half of the last century, antibiotics have become the pillars of modern medicine for fighting bacterial infections. However, pathogens resistant to antibiotic treatment have increased in recent decades, and efforts to discover new antibiotics have decreased. As a result, it is becoming increasingly difficult to treat bacterial infections successfully, and we look forward to more significant efforts from both governments and the scientific community to research new antibacterial drugs. This perspective article highlights the high potential of bacterial transcriptional and posttranscriptional regulators as targets for developing new drugs. We highlight some recent advances in the search for new compounds that inhibit their biological activity and, as such, appear very promising for treating bacterial infections.

In Silico Research of New Therapeutics Rotenoids Derivatives against Leishmania amazonensis Infection

Yearly, 1,500,000 cases of leishmaniasis are diagnosed, causing thousands of deaths. To advance in its therapy, we present an interdisciplinary protocol that unifies ethnobotanical knowledge of natural compounds and the latest bioinformatics advances to respond to an orphan disease such as leishmaniasis and specifically the one caused by Leishmania amazonensis. The use of ethnobotanical information serves as a basis for the development of new drugs, a field in which computer-aided drug design (CADD) has been a revolution. Taking this information from Amazonian communities, located in the area with a high prevalence of this disease, a protocol has been designed to verify new leads. Moreover, a method has been developed that allows the evaluation of lead molecules, and the improvement of their affinity and specificity against therapeutic targets. Through this approach, deguelin has been identified as a good lead to treat the infection due to its potential as an ornithine decarboxylase (ODC) inhibitor, a key enzyme in Leishmania development. Using an in silico-generated combinatorial library followed by docking approaches, we have found deguelin derivatives with better affinity and specificity against ODC than the original compound, suggesting that this approach could be adapted for developing new drugs against leishmaniasis.

The Arsenal of Bioactive Molecules in the Skin Secretion of Urodele Amphibians

Urodele amphibians (∼768 spp.), salamanders and newts, are a rich source of molecules with bioactive properties, especially those isolated from their skin secretions. These include pharmacological attributes, such as antimicrobial, antioxidant, vasoactive, immune system modulation, and dermal wound healing activities. Considering the high demand for new compounds to guide the discovery of new drugs to treat conventional and novel diseases, this review summarizes the characteristics of molecules identified in the skin of urodele amphibians. We describe urodele-derived peptides and alkaloids, with emphasis on their biological activities, which can be considered new scaffolds for the pharmaceutical industry. Although much more attention has been given to anurans, bioactive molecules produced by urodeles have the potential to be used for biotechnological purposes and stand as viable alternatives for the development of therapeutic agents.

Novel Molecular Targets of Antidepressants

Antidepressants target a variety of proteins in the central nervous system (CNS), the most important belonging to the family of G-protein coupled receptors and the family of neurotransmitter transporters. The increasing number of crystallographic structures of these proteins have significantly contributed to the knowledge of their mechanism of action, as well as to the design of new drugs. Several computational approaches such as molecular docking, molecular dynamics, and virtual screening are useful for elucidating the mechanism of drug action and are important for drug design. This review is a survey of molecular targets for antidepressants in the CNS and computer based strategies to discover novel compounds with antidepressant activity.

N-terminal phosphorylation regulates the activity of Glycogen Synthase Kinase 3 from Plasmodium falciparum

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite's life cycle. In the uncanonical N‑terminal region of the parasite enzyme, we identified several autophosphorylation sites and probed their role in activity regulation of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N‑terminus, triggered by N‑terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

ERANET JTC 2011: Submission and Activation of an International Academic Translational Project in Advanced Breast Cancer. Experience From the ET-FES Study

Background: Academic research is important to face unmet medical needs. The Oncological community encounters many hurdles in setting up multicenter investigator-driven trials mainly due to administrative complexity. The purpose of a network organization at a multinational level is to facilitate clinical trials through standardization, coordination, and education for drug development and regulatory approval.Methods: The application of an European grant foresees the creation of a consortium which aims at facilitating multi-center academic clinical trials.Results: The ERA-NET TRANSCAN Call 2011 on “Validation of biomarkers for personalized cancer medicine” was released on December 2011. This project included Italian, Spanish, French and German centers. The approval process included Consortium constitution, project submission, Clinical Trial Submission, and activation on a national level. The different timescales for submitting study documents in each Country and the misalignment of objections by each Competent Authority CA, generated several requests for changes to the study documents which meant amendments had to be made; as requested by the 2001/20/EC Directive, the alignment of core documents is mandatory. This procedure impacted significantly on study activation timelines. Time to first patient in was 14, 10, 28, and 31 months from the date of submission in Italy, France, Spain, and Germany, respectively. Accrual was stopped on 22nd January 2021 due to an 18F FES shortage as the primary reason but also for having exceeded the project deadlines with consequent exhaustion of the funds allocated for the project.Conclusions: Pharmaceutical companies might be reluctant to fund research projects aimed at treatment individualization if the approval for a wider indication has already been achieved. Academic trials therefore become fundamental for promoting trials which are not attractive to big pharma. It was very difficult and time consuming to activate an academic clinical trial, for this reason, a study may become “old” as new drugs entered into the market. National institutions should promote the development of clinical research infrastructures and network with competence in regulatory, ethical, and legal skills to speed up academic research.

Scalable and selective deuteration of (hetero)arenes

Isotope labelling, particularly deuteration, is an important tool for the development of new drugs, specifically for identification and quantification of metabolites. For this purpose, many efficient methodologies have been developed that allow for the small-scale synthesis of selectively deuterated compounds. Due to the development of deuterated compounds as active drug ingredients, there is a growing interest in scalable methods for deuteration. The development of methodologies for large-scale deuterium labelling in industrial settings requires technologies that are reliable, robust and scalable. Here we show that a nanostructured iron catalyst, prepared by combining cellulose with abundant iron salts, permits the selective deuteration of (hetero)arenes including anilines, phenols, indoles and other heterocycles, using inexpensive D2O under hydrogen pressure. This methodology represents an easily scalable deuteration (demonstrated by the synthesis of deuterium-containing products on the kilogram scale) and the air- and water-stable catalyst enables efficient labelling in a straightforward manner with high quality control.

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.