Activity, structure, and diversity of Type II proline-rich antimicrobial peptides from insects.

Apidaecin 1b (Api), the first characterized Type II Proline-rich antimicrobial peptide (PrAMP), is encoded in the honey bee genome. It inhibits bacterial growth by binding in the nascent peptide exit tunnel of the ribosome after the release of the completed protein and trapping the release factors. By genome mining, we have identified 71 PrAMPs encoded in insect genomes as pre-pro-polyproteins.

A Broad Spectrum Lasso Peptide Antibiotic Targeting the Bacterial Ribosome.

Lasso peptides, biologically active molecules with a distinct structurally constrained knotted fold, are natural products belonging to the class of ribosomally-synthesized and posttranslationally modified peptides (RiPPs). Lasso peptides act upon several bacterial targets, but none have been reported to inhibit the ribosome, one of the main antibiotic targets in the bacterial cell. Here, we report the identification and characterization of the lasso peptide antibiotic, lariocidin (LAR), and its internally cyclized derivative, lariocidin B (LAR-B), produced by .

Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms.

Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown.

Predicting Response to Immunotargeted Therapy in Endometrial Cancer via Tumor Immune Microenvironment: A Multicenter, Observational Study.

Only one-third of patients with advanced MSS/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib's ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its effect. These findings underscore the importance of exploring tumor microenvironment parameters to identify markers that can accurately select candidates for this type of therapy.

2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study.

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group.

An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance.

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of , , and . We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits.

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.

The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA.

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion.

The ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr.

Synthesis of β-Carbolines with Electrocyclic Cyclization of 3-Nitrovinylindoles.

The β-carboline motif is common in drug discovery and among numerous biologically active natural products. However, its synthetic preparation relies on multistep sequences and heavily depends on the type of substitution required in the core of the desired β-carboline target. Herein, we demonstrate that this structural motif can be accessed with the microwave-assisted electrocyclic cyclization of heterotrienic aci (alkylideneazinic acid) forms of 3-nitrovinylindoles.

Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.

With the growing crisis of antimicrobial resistance, it is critical to continue to seek out new sources of novel antibiotics. This need has led to renewed interest in natural product antimicrobials, specifically antimicrobial peptides. Nonlytic antimicrobial peptides are highly promising due to their unique mechanisms of action.

One-Pot Synthesis of Polynuclear Indole Derivatives by Friedel-Crafts Alkylation of γ-Hydroxybutyrolactams.

The Friedel-Crafts reaction of novel 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones was used for low cost, one-pot preparation of polycyclic indole derivatives structurally similar to Ergot alkaloids.

An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones.

A straightforward three-step procedure affording a wide range of novel 7-aryl substituted paullone derivatives was developed. This scaffold is structurally similar to 2-(1-indol-3-yl)acetamides-promising antitumor agents-hence, could be useful for the development of a new class of anticancer drugs.

Insights into the ribosome function from the structures of non-arrested ribosome-nascent chain complexes.

During protein synthesis, the growing polypeptide threads through the ribosomal exit tunnel and modulates ribosomal activity by itself or by sensing various small molecules, such as metabolites or antibiotics, appearing in the tunnel. While arrested ribosome-nascent chain complexes (RNCCs) have been extensively studied structurally, the lack of a simple procedure for the large-scale preparation of peptidyl-tRNAs, intermediates in polypeptide synthesis that carry the growing chain, means that little attention has been given to RNCCs representing functionally active states of the ribosome. Here we report the facile synthesis of stably linked peptidyl-tRNAs through a chemoenzymatic approach based on native chemical ligation and use them to determine several structures of RNCCs in the functional pre-attack state of the peptidyl transferase centre.

A Convenient Way to Quinoxaline Derivatives through the Reaction of 2-(3-Oxoindolin-2-yl)-2-phenylacetonitriles with Benzene-1,2-diamines.

Microwave-assisted reaction between 2-(3-oxoindolin-2-yl)-2-phenylacetonitriles andbenzene-1,2-diamines leads to the high-yielding formation of the corresponding quinoxalines as sole, easily isolaable products. The featured transformation involves unusual extrusion of phenylacetonitrile molecule and could be performed in a short sequence starting from commonly available indoles and nitroolefins.

Nitrovinylindoles as Heterotrienes: Electrocyclic Cyclization En Route to β-Carbolines: Total Synthesis of Alkaloids Norharmane, Harmane, and Eudistomin N.

Unusual cascade transformation was developed involving microwave assisted electrocyclic cyclization of aci (alkylideneazinic acid) forms of nitrovinylindoles acting as heterotrienes. Subsequent one-pot reduction allowed for efficient access to β-carbolines, including several natural products, alkaloids norharmane, harmane and eudistomin N.

Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine.

Ribosome serves as a universal molecular machine capable of synthesis of all the proteins in a cell. Small-molecule inhibitors, such as ribosome-targeting antibiotics, can compromise the catalytic versatility of the ribosome in a context-dependent fashion, preventing transpeptidation only between particular combinations of substrates. Classic peptidyl transferase center inhibitor chloramphenicol (CHL) fails to inhibit transpeptidation reaction when the incoming A site acceptor substrate is glycine, and the molecular basis for this phenomenon is unknown.

Synthetic Studies toward 1,2,3,3a,4,8b-Hexahydropyrrolo[3,2-]indole Core. Unusual Fragmentation with 1,2-Aryl Shift.

Base-assisted transformations of 2-(3-oxoindolin-2-yl)acetonitriles were investigated. Unexpectedly, attempted reactions of substrates possessing nonprotected nitrogen atoms were accompanied by unusual extrusions of 2-arylacetonitriles, followed by a 1,2-aryl shift to afford 3-hydroxyindolin-2-ones. On the other hand, the reactions for -alkyl derivatives of oxoindolines took the expected route by only providing 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-]indoles.

Direct Conversion of 3-(2-Nitroethyl)-1-Indoles into 2-(1-Indol-2-yl)Acetonitriles.

The recently discovered [4+1]-spirocyclization of nitroalkenes to indoles provided a convenient new approach to 2-(1-indol-2-yl)acetonitriles. However, this reaction was complicated by the formation of inert 3-(2-nitroethyl)-1-indole byproducts. Herein, we offer a workaround this problem that allows for effective transformation of the unwanted byproducts into acetonitrile target molecules.

The Role of Release Factors in the Hydrolysis of Ester Bond in Peptidyl-tRNA.

Class I release factors (RFs) recognize stop codons in the sequences of mRNAs and are required for the hydrolysis of peptidyl-tRNA in the ribosomal P site during the final step of protein synthesis in bacteria, resulting in the release of a complete polypeptide chain from the ribosome. A key role in this process belongs to the highly conserved GGQ motif in RFs. Mutations in this motif can reduce the hydrolysis rate or even completely inhibit the reaction.

Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.

Many antibiotics inhibit bacterial growth by binding to the ribosome and interfering with protein biosynthesis. Macrolides represent one of the most successful classes of ribosome-targeting antibiotics. The main clinically relevant mechanism of resistance to macrolides is dimethylation of the 23S rRNA nucleotide A2058, located in the drug-binding site, a reaction catalyzed by Erm-type rRNA methyltransferases.

Preparation of spiro[indole-3,5'-isoxazoles] Grignard conjugate addition/spirocyclization sequence.

A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Brønsted acid-assisted spirocyclization allowed for preparation of 4'-spiro[indole-3,5'-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4'-alkylsubstituted derivatives hardly available by other means.

Preparation of Stereodefined 2-(3-Oxoindolin-2-yl)-2-Arylacetonitriles via One-Pot Reaction of Indoles with Nitroalkenes.

Recently discovered reactivity of nitrostyrenes in phosphorous acid to facilitate the diastereoselective [4 + 1]-cycloaddition of indoles in combination with unusual oxazoline ring cleavage and subsequent 1,2-alkyl shift afforded stereochemically defined 2-(3-oxoindolin-2-yl)-2-arylacetonitriles as sole products.

Synthesis of Spiro[indole-3,5'-isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles.

An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4' H-spiro[indole-3,5'-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.

Effects of early-life stress and HDAC inhibition on maternal behavior in mice.

Despite the well-established fact that maternal care plays a pivotal role in the offspring development, little is known about the effects of disruption of maternal care early in life on the development of this behavior in the offspring. Using brief repeated maternal separation (45 min/day on postnatal Days 3-6), which represents a model of early life stress, we found behavioral changes in adult female mice offspring. The decrease in home cage exploratory behavior (both pup-directed and nonpup-directed) was revealed later in adulthood without changes in maternal care level.

Rituximab Downregulates Gene Expression Associated with Cell Proliferation, Survival, and Proteolysis in the Peripheral Blood from Rheumatoid Arthritis Patients: A Link between High Baseline Autophagy-Related ULK1 Expression and Improved Pain Control.

Objective. To clarify molecular mechanisms for the response to rituximab in a longitudinal study. Methods.