[Antibiotic Resistance: Threats and Search for Solution].

Antibiotic and, more broadly, antimicrobial resistance is a naturally occurring biological phenomenon and a major public health problem. Mass emergence of drug-resistant bacterial strains was first observed in the mid-20th century. Since then, cases of resistance have been reported worldwide, and multidrug resistance has been increasingly reported over the past two decades.

Enzymatic Synthesis of Biologically Active -Phosphinic Analogue of α-Ketoglutarate.

Amino acid analogues with a phosphorus-containing moiety replacing the carboxylic group are promising sources of biologically active compounds. The -phosphinic group, with hydrogen-phosphorus-carbon (H-P-C) bonds and a flattened tetrahedral configuration, is a bioisostere of the carboxylic group. Consequently, amino--phosphinic acids undergo substrate-like enzymatic transformations, leading to new biologically active metabolites.

Dual-Reporter SARS-CoV-2 Replicon for Screening Viral Polymerase Inhibitors.

To design a safe cellular system for testing inhibitors targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, a genetic construct was engineered containing viral cDNA with two blocks of reporter genes while the genes encoding structural S, E, and M proteins were absent. The first reporter block, consisting of Renilla luciferase and green fluorescent protein (Rluc-GFP), was located upstream of the SARS-CoV-2 5'-UTR. Meanwhile, the second block represented by firefly luciferase and red fluorescent protein (Fluc-RFP) was positioned downstream of the transcription regulatory sequence (TRS-N).

[Cytotoxicity Studies of 5-Arylaminouracil Derivatives].

We have previously shown that 5-arylaminouracil derivatives can inhibit HIV-1, herpesviruses, mycobacteria, and other pathogens through various mechanisms. The purpose of this study was to evaluate the potential of 5-arylaminouracils and their derivatives against leukemia, neuroblastoma, and glial brain tumors. 5-Aminouracils with various substituents and their 5'-norcabocyclic and ribo derivatives were screened for cytotoxicity against two neuroblastoma cell lines (SH-SY5Y and IMR-32), K-562 lymphoblastic cells, HL-60 promyeoloblastic cells, and low-passage variants of well-differentiated glioblastoma multiforme (GBM5522 and GBM6138).

Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids.

The mechanisms of action of pyrimidine nucleoside derivatives on model lipid membranes of various compositions were studied. A systematic analysis of the tested agents' effects on the membrane physicochemical properties was performed. Differential scanning microcalorimetry data indicated that the ability of nucleoside derivatives to disorder membrane lipids depended on the types of nucleoside bases and membrane-forming lipids.

Polyamine Catabolism Revisited: Acetylpolyamine Oxidase Plays a Minor Role due to Low Expression.

Biogenic polyamines are ubiquitous compounds. Dysregulation of their metabolism is associated with the development of various pathologies, including cancer, hyperproliferative diseases, and infections. The canonical pathway of polyamine catabolism includes acetylation of spermine and spermidine and subsequent acetylpolyamine oxidase (PAOX)-mediated oxidation of acetylpolyamines (back-conversion) or their direct efflux from the cell.

In-Cell Testing of Zinc-Dependent Histone Deacetylase Inhibitors in the Presence of Class-Selective Fluorogenic Substrates: Potential and Limitations of the Method.

The development of anticancer drugs based on zinc-dependent histone deacetylase inhibitors (HDACi) has acquired great practical significance over the past decade. The most important HDACi characteristics are selectivity and strength of inhibition since they determine the mechanisms of therapeutic action. For in-cell testing of the selectivity of de novo-synthesized HDACi, Western blot analysis of the level of acetylation of bona fide protein substrates of HDACs of each class is usually used.

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.

Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected.

New Biocides Based on -Alkylcytidines: Effects on Microorganisms and Application for the Protection of Cultural Heritage Objects of Painting.

The rapid increase in the antibiotic resistance of microorganisms, capable of causing diseases in humans as destroying cultural heritage sites, is a great challenge for modern science. In this regard, it is necessary to develop fundamentally novel and highly active compounds. In this study, a series of -alkylcytidines, including 5- and 6-methylcytidine derivatives, with extended alkyl substituents, were obtained in order to develop a new generation of antibacterial and antifungal biocides based on nucleoside derivatives.

New Flexible Analogues of 8-Aza-7-deazapurine Nucleosides as Potential Antibacterial Agents.

A variety of ribo-, 2'-deoxyribo-, and 5'-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for antibacterial activity. Both chemical and chemoenzymatic methods of synthesis for the 8-aza-7-deazainosine fleximers were compared. In the case of the 8-aza-7-deazahypoxanthine fleximer, the transglycosylation reaction proceeded with the formation of side products.

A Desmethylphosphinothricin Dipeptide Derivative Effectively Inhibits and Growth.

New antibiotics are unquestionably needed to fight the emergence and spread of multidrug-resistant bacteria. To date, antibiotics targeting bacterial central metabolism have been poorly investigated. By determining the minimal inhibitory concentration (MIC) of desmethylphosphinothricin (Glu-γ-P), an analogue of glutamate with a phosphinic moiety replacing the γ-carboxyl group, we previously showed its promising antibacterial activity on .

5-Substituted Uridines with Activity against Gram-Positive Bacteria.

The emergence of drug-resistant strains of pathogenic microorganisms necessitates the creation of new drugs. A series of uridine derivatives containing an extended substituent at the C-5 position as well as C-5 alkyloxymethyl, alkylthiomethyl, alkyltriazolylmethyl, alkylsulfinylmethyl and alkylsulfonylmethyl uridines were obtained in order to explore their antimicrobial properties and solubility. It has been shown that new ribonucleoside derivatives have an order of magnitude better solubility in water compared to their 2'-deoxy analogues and effectively inhibit the growth of a number of Gram-positive bacteria, including resistant strains of Mycobacterium smegmatis (MIC=15-200 μg/mL) and Staphylococcus aureus (MIC=25-100 μg/mL).

[Interaction of DNA Methyltransferase Dnmt3a with Phosphorus Analogs of S-Adenosylmethionine and S-Adenosylhomocysteine].

Enzymatic methyltransferase reactions are of crucial importance for cell metabolism. S-Adenosyl-L-methionine (AdoMet) is a main donor of the methyl group. DNA, RNA, proteins, and low-molecular-weight compounds are substrates of methyltransferases.

-Methylated Spermidine Derivatives: Convenient Syntheses and Antizyme-Related Effects.

The biogenic polyamines, spermidine (Spd) and spermine (Spm), are present at millimolar concentrations in all eukaryotic cells, where they participate in the regulation of vitally important cellular functions. Polyamine analogs and derivatives are a traditional and important instrument for the investigation of the cellular functions of polyamines, enzymes of their metabolism, and the regulation of the biosynthesis of antizyme-a key downregulator of polyamine homeostasis. Here, we describe convenient gram-scale syntheses of a set of -methylated analogs of Spd.

Synthesis of 1-[ω-(Bromophenoxy)alkyl]-3-naphthalenylmethyl Derivatives of Uracil and Their Analogues As Probable Inhibitors of Human Cytomegalovirus Replication.

The synthesis of a new series of 1-[ω-(bromophenoxy)alkyl]-uracil derivatives containing in position 3 naphthalen-1-yl-, naphthalen-2-yl-, 1-bromonaphthalen-2-ylmethyl, benzyl, and anthracene 9-methyl fragment was carried out. The antiviral properties of the synthesized compounds were studied against human cytomegalovirus. It was found that the compound that contained a bridge of five methylene groups has a high anti-cytomegalovirus activity in vitro.

[How Histone Deacetylase 3 Controls Hepcidin Expression and Hepatitis C Virus Replication].

The key role of histone deacetylases (HDAC) in the regulation of the cellular response to infection with the hepatitis C virus (HCV) was first demonstrated in 2008. When studying the metabolism of iron in the liver tissues of patients with chronic hepatitis C, the authors found that the expression of the hepcidin gene (HAMP), a hormone regulator of iron export, is markedly reduced in hepatocytes under conditions of oxidative stress caused by viral infection. HDAC were involved in the regulation of hepcidin expression through the control of acetylation level of histones and transcription factors, primarily STAT3, associated with the HAMP promoter.

Transcriptome Analysis of Redox Systems and Polyamine Metabolic Pathway in Hepatoma and Non-Tumor Hepatocyte-like Cells.

Reactive oxygen species (ROS) play a major role in the regulation of various processes in the cell. The increase in their production is a factor contributing to the development of numerous pathologies, including inflammation, fibrosis, and cancer. Accordingly, the study of ROS production and neutralization, as well as redox-dependent processes and the post-translational modifications of proteins, is warranted.

Synthesis of the Indole-Based Inhibitors of Bacterial Cystathionine γ-Lyase NL1-NL3.

Bacterial cystathionine γ-lyase (bCSE) is the main producer of HS in pathogenic bacteria such as , , etc. The suppression of bCSE activity considerably enhances the sensitivity of bacteria to antibiotics. Convenient methods for the efficient synthesis of gram quantities of two selective indole-based bCSE inhibitors, namely (2-(6-bromo-1-indol-1-yl)acetyl)glycine (NL1), 5-((6-bromo-1-indol-1-yl)methyl)- 2-methylfuran-3-carboxylic acid (NL2), as well as a synthetic method for preparation 3-((6-(7-chlorobenzo[]thiophen-2-yl)-1-indol-1-yl)methyl)- 1-pyrazole-5-carboxylic acid (NL3), have been developed.

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response.

Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma.

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA.

The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task.

Synthesis of 1-[ω-(Bromophenoxy)alkyl]-3-Naphthalenylmethyl Uracil Derivatives and Their Analogues as Probable Inhibitors of Human Cytomegalovirus Replication.

A new series of 1-[ω-(bromophenoxy)alkyl]-uracil derivatives containing naphthalen-1-yl, naphthalen-2-yl, 1-bromonaphthalen-2-ylmethyl, benzyl, and anthracene-9-ylmethyl fragments in position 3 of uracil residue was synthesized. The antiviral properties of the synthesized compounds against human cytomegalovirus were studied. It was found that the compound containing a bridge consisting of five methylene groups exhibits a high anti-cytomegalovirus activity in vitro.

Antibacterial Activity of Peptide Derivatives of Phosphinothricin against Multidrug-Resistant .

The fast spread of bacteria that are resistant to many classes of antibiotics (multidrug resistant) is a global threat to human and animal health with a worrisome scenario ahead. Novel therapeutical strategies are of crucial importance to combat this phenomenon. For this purpose, we investigated the antimicrobial properties of the naturally occurring tripeptide Bialaphos and a dipeptide -leucyl--phosphinoithricin, the synthesis and diastereomers separation of which are herein described.

Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP.

The great interest in studying the structure of human purine nucleoside phosphorylase (PNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, PNP inhibitors are used in organ transplant surgeries to provide immunodeficiency during and after the procedure. Previously, we showed that members of the well-known fleximer class of nucleosides are substrates of PNP.