Topoisomerase Research Articles

Genome Stability Profiles of Titania Nanosurface Technology for Biomedical Applications

The emergence of nano-based products for advanced biomedical applications has underlined the need for toxicogenomic studies which govern genome stability endpoints. In the present study, the genome stability profiles on cell-TNA interaction were assessed via nuclear staining profile by a fluorescent microscope, DNA ploidy profile by flow-cytometry, metaphase chromosome analysis, DNA topoisomerase II alpha (TOP2A) profiling by chromogenic in situ hybridization (CISH), cytokinesis-blocked micronucleus assay (CBMN), reactive oxygen species (ROS) measurement and gene expression profile by real-time polymerase chain reaction (RT-PCR). Findings from this study demonstrated that no significant genomic instability risk was observed from cell-TNA interaction, especially at clastogenic and aneugenic levels. Findings also suggest that cell-TNA interaction could involve the regulation of ribonucleoprotein complex and cell metabolism associated with the cellular adaptation process towards the nanosurface. Further comprehensive studies involving in vivo models are needed to support this work.

Coinhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription.

Pancreatic carcinoma lacks effective therapeutic strategies resulting in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC affects initiation, development, and survival of this tumor type. Using patient-derived xenografts of KRAS- and MYC-driven pancreatic carcinoma, we show that coinhibition of topoisomerase 1 (TOP1) and bromodomain-containing protein 4 (BRD4) synergistically induces tumor regression by targeting promoter pause release. Comparing the nascent transcriptome with the recruitment of elongation and termination factors, we found that coinhibition of TOP1 and BRD4 disrupts recruitment of transcription termination factors. Thus, RNA polymerases transcribe downstream of genes for hundreds of kilobases leading to readthrough transcription. This occurs during replication, perturbing replisome progression and inducing DNA damage. The synergistic effect of TOP1 + BRD4 inhibition is specific to cancer cells leaving normal cells unaffected, highlighting the tumor's vulnerability to transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of transcription and replication.

Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

Regulation of global transcription output is important for normal development and disease, but little is known about the mechanisms involved. DNA topoisomerase I (TOP1) is an enzyme well-known for its role in relieving DNA supercoils for enabling transcription. Here, we report a non-enzymatic function of TOP1 that downregulates RNA synthesis. This function is dependent on specific DNA-interacting residues located on a conserved protein surface. A loss-of-function knock-in mutation on this surface, R548Q, is sufficient to cause hypertranscription and alter differentiation outcomes in mouse embryonic stem cells (mESCs). Hypertranscription in mESCs is accompanied by reduced TOP1 chromatin binding and change in genomic supercoiling. Notably, the mutation does not impact TOP1 enzymatic activity; rather, it diminishes TOP1-DNA binding and formation of compact protein-DNA structures. Thus, TOP1 exhibits opposing influences on transcription through distinct activities which are likely to be coordinated. This highlights TOP1 as a safeguard of appropriate total transcription levels in cells.

Synthesis, Physicochemical Characterization using a Facile Validated HPLC Quantitation Analysis Method of 4-Chloro-phenylcarbamoyl-methyl Ciprofloxacin and Its Biological Investigations.

A novel derivative of ciprofloxacin (Cpx) was synthesized and characterized using various analytical techniques, including FT-IR spectroscopy, UV-Vis spectroscopy, TEM and SEM analysis, 1H NMR, 13C NMR, and HPLC analysis. The newly prepared Cpx derivative (Cpx-Drv) exhibited significantly enhanced antibacterial properties compared to Cpx itself. In particular, Cpx-Drv demonstrated a 51% increase in antibacterial activity against S. aureus and a 30% improvement against B. subtilis. It displayed potent inhibitory effects on topoisomerases II (DNA gyrase and topoisomerase IV) as potential molecular targets, with IC50 values of 6.754 and 1.913 µg/mL, respectively, in contrast to Cpx, which had IC50 values of 2.125 and 0.821 µg/mL, respectively. Docking studies further supported these findings, showing that Cpx-Drv exhibited stronger binding interactions with the gyrase enzyme (PDB ID: 2XCT) compared to the parent Cpx, with binding affinities of -10.3349 and -7.7506 kcal/mole, respectively.

To Break or Not to Break: The Role of TOP2B in Transcription.

Transcription and its regulation pose challenges related to DNA torsion and supercoiling of the DNA template. RNA polymerase tracking the helical groove of the DNA introduces positive helical torsion and supercoiling upstream and negative torsion and supercoiling behind its direction of travel. This can inhibit transcriptional elongation and other processes essential to transcription. In addition, chromatin remodeling associated with gene activation can generate or be hindered by excess DNA torsional stress in gene regulatory regions. These topological challenges are solved by DNA topoisomerases via a strand-passage reaction which involves transiently breaking and re-joining of one (type I topoisomerases) or both (type II topoisomerases) strands of the phosphodiester backbone. This review will focus on one of the two mammalian type II DNA topoisomerase enzymes, DNA topoisomerase II beta (TOP2B), that have been implicated in correct execution of developmental transcriptional programs and in signal-induced transcription, including transcriptional activation by nuclear hormone ligands. Surprisingly, several lines of evidence indicate that TOP2B-mediated protein-free DNA double-strand breaks are involved in signal-induced transcription. We discuss the possible significance and origins of these DSBs along with a network of protein interaction data supporting a variety of roles for TOP2B in transcriptional regulation.

Retracted: DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway.

[This retracts the article DOI: 10.1155/2022/4277254.].

Utilizing coordination chemistry through formation of a CuII-quinalizarin complex to manipulate cell biology: An in vitro, in silico approach

Quinalizarin, an analogue of anthracycline anticancer agents, is an anticancer agent itself. A CuII complex was prepared and characterized by elemental analysis, UV-Vis & IR spectroscopy, mass spectrometry, EPR and DFT. The intention behind the preparation of the complex was to increase cellular uptake, compare its binding with DNA against that of quinalizarin, modulation of semiquinone formation, realization of human DNA topoisomerase I & human DNA topoisomerase II inhibition and observation of anticancer activity. While the first two attributes of complex formation lead to increased efficacy, decrease in semiquinone generation could results in a compromise with efficacy. Inhibition of human DNA topoisomerase makes up this envisaged compromise in free radical activity since the complex shows remarkable ability to disrupt activities of human DNA topoisomerase I and II. The complex unlike quinalizarin, does not catalyze flow of electrons from NADH to O2 to the extent known for quinalizarin. Hence, decrease in semiquinone or superoxide radical anion could make modified quinalizarin [as CuII complex] less efficient in free radical pathway. However, it would be less cardiotoxic and that would be advantageous to qualify it as a better anticancer agent. Although binding to calf thymus DNA was comparable to quinalizarin, it was weaker than anthracyclines. Low cost of quinalizarin could justify consideration as a substitute for anthracyclines but the study revealed IC50 of quinalizarin/CuII-quinalizarin was much higher than anthracyclines or their complexes. Even then, there is a possibility that CuII-quinalizarin could be an improved and less costly form of quinalizarin as anticancer agent.

Novel bacterial topoisomerase inhibitors: unique targeting activities of amide enzyme-binding motifs for tricyclic analogs.

Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of antibacterial agents with a unique binding mode and distinct pharmacology that enables them to evade existing resistance mechanisms. The clinical development of NBTIs has been plagued by several issues, including cardiovascular safety. Herein, we report a sub-series of tricyclic NBTIs bearing an amide linkage that displays promising antibacterial activity, potent dual-target inhibition of DNA gyrase and topoisomerase IV (TopoIV), as well as improved cardiovascular safety and metabolic profiles. These amide NBTIs induced both single- and double-strand breaks in pBR322 DNA mediated by Staphylococcus aureus DNA gyrase, in contrast to prototypical NBTIs that cause only single-strand breaks. Unexpectedly, amides 1a and 1b targeted human topoisomerase IIα (TOP2α) causing both single- and double-strand breaks in pBR322 DNA, and induced DNA strand breaks in intact human leukemia K562 cells. In addition, anticancer drug-resistant K/VP.5 cells containing decreased levels of TOP2α were cross-resistant to amides 1a and 1b. Together, these results demonstrate broad spectrum antibacterial properties of selected tricyclic NBTIs, desirable safety profiles, an unusual ability to induce DNA double-stranded breaks, and activity against human TOP2α. Future work will be directed toward optimization and development of tricyclic NBTIs with potent and selective activity against bacteria. Finally, the current results may provide an additional avenue for development of selective anticancer agents.

Commensal Fitness Advantage May Contribute to the Global Dissemination of Multidrug-Resistant Lineages of Bacteria-The Case of Uropathogenic E. coli.

It is widely accepted that favorable fitness in commensal colonization is one of the prime facilitators of clonal dissemination in bacteria. The question arises as to what kind of fitness advantage may be wielded by uropathogenic strains of the two predominant fluoroquinolone- and multidrug-resistant clonal groups of E. coli-ST131-H30 and ST1193, which has permitted their unprecedented pandemic-like global expansion in the last few decades. The colonization-associated genes' content, carriage of low-cost plasmids, and integrons with weak promoters could certainly contribute to the fitness of the pandemic groups, although those genetic factors are common among other clonal groups as well. Also, ST131-H30 and ST1193 strains harbor fluoroquinolone-resistance conferring mutations targeting serine residues in DNA gyrase (GyrA-S83) and topoisomerase IV (ParC-S80) that, in those clonal backgrounds, might result in a commensal fitness benefit, i.e., beyond the antibiotic resistance per se. This fitness gain might have contributed not only to the widespread dissemination of these major clones in the healthcare setting but also to their long-term colonization of healthy individuals and, thus, circulation in the community, even in a low or no fluoroquinolone use environment. This evolutionary shift affecting commensal E. coli, initiated by mutations co-favorable in both antibiotics-treated patients and healthy individuals warrants more in-depth studies to monitor further changes in the epidemiological situation and develop effective measures to reduce the antibiotic resistance spread.

Computational evaluation of phytochemicals targeting DNA topoisomerase I in Leishmania donovani: molecular docking and molecular dynamics simulation studies

DNA topoisomerase I (Topo I) is a ubiquitous enzyme that plays a crucial role in resolving the topological constraints of supercoiled DNA during various cellular activities, including repair, replication, recombination, transcription, and chromatin remodeling. Multiple studies have confirmed the essential role of Topo I in nucleic acid metabolism of Leishmania donovani, the kinetoplastid parasite responsible for visceral leishmaniasis or kala-azar. Inhibition of this enzyme has shown promise as a strategy for therapy against visceral leishmaniasis. However, current treatment options suffer from limitations related to effectiveness, cost, and side effects. To address these challenges, computational methods have been employed in this study to investigate the inhibition of Leishmania donovani DNA topoisomerase I (LdTopo I) by phytochemicals derived from Indian medicinal plants known for their anti-leishmanial activity. A library of phytochemicals and known inhibitors was assembled, and virtual screening based on docking binding affinities was conducted to identify potent phytochemical inhibitors. To assess the drug-likeness of the docked phytochemicals, their physicochemical properties were predicted. Additionally, molecular dynamics (MD) simulations were performed on the docked complexes for a duration of 100 ns to evaluate their stability, intermolecular interactions, and dynamic behavior. Among all the docked phytochemicals, three compounds, namely CID23266147 (withanolide N), CID5488537 (fagopyrine), and CID100947536 (isozeylanone), exhibited the highest inhibitory potential against LdTopo I. These findings hold promise for the development of novel inhibitors targeting LdTopo I, which could potentially lead to improved therapies for visceral leishmaniasis. Communicated by Ramaswamy H. Sarma

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis.

Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 N4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using in silico, in vitro, and in vivo approaches. Several compounds displayed interesting activities against both Gram-negative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic in vitro assays. Phenotypic analysis of both Escherichia coli and Bacillus subtilis confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the B. subtilis cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones.

Narciclasine, a novel topoisomerase I inhibitor, exhibited potent anti-cancer activity against cancer cells

DNA topoisomerases are essential nuclear enzymes in correcting topological DNA errors and maintaining DNA integrity. Topoisomerase inhibitors are a significant class of cancer chemotherapeutics with a definite curative effect. Natural products are a rich source of lead compounds for drug discovery, including anti-tumor drugs. In this study, we found that narciclasine (NCS), an amaryllidaceae alkaloid, is a novel inhibitor of topoisomerase I (topo I). Our data demonstrated that NCS inhibited topo I activity and reversed its unwinding effect on p-HOT DNA substrate. However, it had no obvious effect on topo II activity. The molecular mechanism of NCS inhibited topo I showed that NCS did not stabilize topo-DNA covalent complexes in cells, indicating that NCS is not a topo I poison. A blind docking result showed that NCS could bind to topo I, suggesting that NCS might be a topo I suppressor. Additionally, NCS exhibited a potent anti-proliferation effect in various cancer cells. NCS arrested the cell cycle at G2/M phase and induced cell apoptosis. Our study reveals the antitumor mechanisms of NCS and provides a good foundation for the development of anti-cancer drugs based on topo I inhibition.Graphical abstract

A Four-Gene Panel for the Prediction of Prognosis and Immune Cell Enrichment in Gliomas.

Gliomas is a deadly disease without effective therapy. Although immunotherapy has provided novel choices for glioma treatment, the curative efficacy is unsatisfactory due to the complex immune micro-environment and the heterogeneity of the disease. Therefore, it is urgent to identify effective biomarkers and therapeutic targets. Overall survival, gene ontology (GO), Kyoto Encyclopedia of Genes, and Genomes (KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and immune infiltration were analyzed by bioinformatics software with The Cancer Genome Atlas (TCGA) database. Based on the TCGA database and protein-protein interaction (PPI) analysis revealed a four-gene panels [DNA topoisomerase II alpha (TOP2A); ribonucleotide reductase regulatory subunit M2 (RRM2); kinesin family member 20A (KIF20A) and DLG associated protein 5 (DLGAP5)], which correlated with poor prognosis, including overall survival (OS), disease specific survival (DSS) and progress free interval (PFI), mitosis, cell cycle, Th2 cells and macrophages enrichment. The four-gene panels correlates with the biomarkers of Th2 cells, macrophages tumor-associated macrophages (TAMs) and the immune checkpoint molecules in gliomas. The four-gene panels represented a novel prognostic indicator and potential therapeutic target for the treatment of glioma. In addition, the four-gene panels might contribute to enhance the efficacy of immunotherapy in glioma.

Molecular Docking Studies of an Isolated Angucycline of Stereospermum fimbriatum, a Novel Anti-MRSA Agent

A novel angucycline, C1 isolated from Stereospermum fimbriatum stem bark was subjected to molecular docking studies on five main targets of penicillin-binding protein 2a (PBP2a), β-lactamase, DNA topoisomerase IV, dehydrosqualene synthase (CrtM) and sortase A (SrtA) for anti-MRSA activity. The binding sites and docking scores of known inhibitors (positive control) were compared with C1. Docking analysis was carried out by AutoDock 4.0 package. The binding site of C1 closely resembled the positive control in all screened receptors. Inhibition constant of C1 was lower than the positive control tested for PBP2a, β-lactamase, dehydrosqualene synthase and sortase A except against DNA Topoisomerase IV. Structure-activity relationship (SAR) analysis of C1 showed that 7-CO was the most significant contributor to its activity since it formed hydrogen bonds with four of the five screened receptors. Molecular docking of C1 indicated that C1 can be a good candidate for new anti-MRSA drug development.

A novel binding site between the voltage-dependent calcium channel CaV1.2 subunit and CaVβ2 subunit discovered using a new analysis method for protein–protein interactions

We developed a new method to analyze protein–protein interactions using a dual-inducible prokaryotic expression system. To evaluate protein–protein binding, a chimeric fusion toxin gene was constructed using a DNase-treated short DNA fragment (epitope library) and CcdB, which encodes a DNA topoisomerase II toxin. Protein–protein interactions would affect toxin activity, resulting in colony formation. Using this novel system, we found a new binding site in the voltage-dependent calcium channel α1 subunit (CaV1.2) for the voltage-dependent calcium channel β2 subunit. Prokaryotic expression screening of the β2 subunit using an epitope library of CaV1.2 resulted in two overlapping clones of the C-terminal sequence of CaV1.2. In vitro overlay and immunoprecipitation analyses revealed preferential binding of the C-terminal sequences of CaV1.2 and β2.

Integrated multi-omics analyses reveal Jorunnamycin A as a novel suppressor for muscle-invasive bladder cancer by targeting FASN and TOP1

BackgroundBladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an urgent need to develop new drugs with low toxicity and high efficiency for MIBC because existing medication has defects, such as high toxicity, poor efficacy, and side effects. Jorunnamycin A (JorA), a natural marine compound, has been found to have a high efficiency anticancer effect, but its anticancer function and mechanism on bladder cancer have not been studied.MethodsTo examine the anticancer effect of JorA on MIBC, Cell Counting Kit 8, EdU staining, and colony formation analyses were performed. Moreover, a xenograft mouse model was used to verify the anticancer effect in vivo. To investigate the pharmacological mechanism of JorA, high-throughput quantitative proteomics, transcriptomics, RT-qPCR, western blotting, immunofluorescence staining, flow cytometry, pulldown assays, and molecular docking were performed.ResultsJorA inhibited the proliferation of MIBC cells, and the IC50 of T24 and UM-UC-3 was 0.054 and 0.084 μM, respectively. JorA-induced significantly changed proteins were enriched in “cancer-related pathways” and “EGFR-related signaling pathways”, which mainly manifested by inhibiting cell proliferation and promoting cell apoptosis. Specifically, JorA dampened the DNA synthesis rate, induced phosphatidylserine eversion, and inhibited cell migration. Furthermore, it was discovered that fatty acid synthase (FASN) and topoisomerase 1 (TOP1) are the JorA interaction proteins. Using DockThor software, the 3D docking structures of JorA binding to FASN and TOP1 were obtained (the binding affinities were − 8.153 and − 7.264 kcal/mol, respectively).ConclusionsThe marine compound JorA was discovered to have a specific inhibitory effect on MIBC, and its potential pharmacological mechanism was revealed for the first time. This discovery makes an important contribution to the development of new high efficiency and low toxicity drugs for bladder cancer therapy.Graphical

Identification of key genes and biological pathways in lung adenocarcinoma by integrated bioinformatics analysis.

The objectives of this study were to identify hub genes and biological pathways involved in lung adenocarcinoma (LUAD) via bioinformatics analysis, and investigate potential therapeutic targets. To determine reliable prognostic biomarkers for early diagnosis and treatment of LUAD. To identify potential therapeutic targets for LUAD, two microarray datasets derived from the Gene Expression Omnibus (GEO) database were analyzed, GSE3116959 and GSE118370. Differentially expressed genes (DEGs) in LUAD and normal tissues were identified using the GEO2R tool. The Hiplot database was then used to generate a volcanic map of the DEGs. Weighted gene co-expression network analysis was conducted to cluster the genes in GSE116959 and GSE118370 into different modules, and identify immune genes shared between them. A protein-protein interaction network was established using the Search Tool for the Retrieval of Interacting Genes database, then the CytoNCA and CytoHubba components of Cytoscape software were used to visualize the genes. Hub genes with high scores and co-expression were identified, and the Database for Annotation, Visualization and Integrated Discovery was used to perform enrichment analysis of these genes. The diagnostic and prognostic values of the hub genes were calculated using receiver operating characteristic curves and Kaplan-Meier survival analysis, and gene-set enrichment analysis was conducted. The University of Alabama at Birmingham Cancer data analysis portal was used to analyze relationships between the hub genes and normal specimens, as well as their expression during tumor progression. Lastly, validation of protein expression was conducted on the identified hub genes via the Human Protein Atlas database. Three hub genes with high connectivity were identified; cellular retinoic acid binding protein 2 (CRABP2), matrix metallopeptidase 12 (MMP12), and DNA topoisomerase II alpha (TOP2A). High expression of these genes was associated with a poor LUAD prognosis, and the genes exhibited high diagnostic value. Expression levels of CRABP2, MMP12, and TOP2A in LUAD were higher than those in normal lung tissue. This observation has diagnostic value, and is linked to poor LUAD prognosis. These genes may be biomarkers and therapeutic targets in LUAD, but further research is warranted to investigate their usefulness in these respects.

Genetic analysis of emerging fungal pathogens: Trichosporon asahii

Trichosporon asahii is an emerging opportunistic fungus that mainly causes fatal disseminated trichosporonosis, especially in immunocompromised patients. T. asahii infection has been reported in Thailand, but few studies of this fungus have been published. Therefore, this study investigated the genetic diversity of 51 clinical strains of T. asahii from urine samples in Thailand. We sequenced and characterized the beta-1-tubulin (TUB1), copper-exporting ATPase (ATP), phosphate carrier protein (PHCP), and topoisomerase-1 (TOP1) genes. In addition, intergenic spacer 1 (IGS1) sequences from our previous studies were investigated. The numbers of haplotypes were 3, 3, 2, 2, and 2 for IGS1, TUB1, ATP, PHCP, and TOP1, respectively. The results suggested a relatively low level of genetic diversity among the strains. The findings illustrated that IGS1, TUB1, ATP, PHCP, and TOP1 can be collectively used as an alternative molecular typing tool for investigating the population diversity and structure of T. asahii.

Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia

Mutations in TDP2, encoding tyrosyl-DNA phosphodiesterase 2, have been associated with a syndromal form of autosomal recessive spinocerebellar ataxia, type 23 (SCAR23). This is a very rare and progressive neurodegenerative disorder described in only nine patients to date, and caused by splice site or nonsense mutations that result in greatly reduced or absent TDP2 protein. TDP2 is required for the rapid repair of DNA double-strand breaks induced by abortive DNA topoisomerase II (TOP2) activity, important for genetic stability in post-mitotic cells such as neurons. Here, we describe a sibship that is homozygous for the first TDP2 missense mutation (p.Glu152Lys) and which presents with clinical features overlapping both SCAR23 and Fanconi anemia (FA). We show that in contrast to previously reported SCAR23 patients, fibroblasts derived from the current patient retain significant levels of TDP2 protein. However, this protein is catalytically inactive, resulting in reduced rates of repair of TOP2-induced DNA double-strand breaks and cellular hypersensitivity to the TOP2 poison, etoposide. The TDP2-mutated patient-derived fibroblasts do not display increased chromosome breakage following treatment with DNA crosslinking agents, but both TDP2-mutated and FA cells exhibit increased chromosome breakage in response to etoposide. This suggests that the FA pathway is required in response to TOP2-induced DNA lesions, providing a possible explanation for the clinical overlap between FA and the current TDP2-mutated patients. When reviewing the relatively small number of patients with SCAR23 that have been reported, it is clear that the phenotype of such patients can extend beyond neurological features, indicating that the TDP2 protein influences not only neural homeostasis but also other tissues as well.

Polyheterocyclic peptidomimetics: Parallel solid phase synthesis of oligo cyclic guanidines and their inhibition activity against Mycobacterium tuberculosis DNA gyrase

Polyheterocycles are one of the most desired synthetic targets due to their numerous and valuable applications in various fields. We report the design and the parallel synthesis of novel linear oligocyclic guanidine peptidomimetics from predesigned reduced polyamides. A screening of these compounds identified active Mycobacterium tuberculosis DNA gyrase inhibitors which do not inhibit human DNA topoisomerase IIα and topoisomerase I.