Hydroxylation and fluorination of proline alters the pyrrolidine ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent fashion, affecting molecular recognition of ...proline-containing molecules by biological systems. While hydroxyprolines and fluoroprolines are common motifs in medicinal and biological chemistry, the synthesis and molecular properties of prolines containing both modifications, i.e., fluoro-hydroxyprolines, have not been described. Here we present a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines (F-Hyps), starting from readily available 4-oxo-l-proline derivatives. Small-molecule X-ray crystallography, NMR spectroscopy, and quantum mechanical calculations are consistent with fluorination at C3 having negligible effects on the hydrogen bond donor capacity of the C4 hydroxyl, but inverting the natural preference of Hyp from C4-exo to C4-endo pucker. In spite of this, F-Hyps still bind to the von Hippel–Lindau (VHL) E3 ligase, which naturally recognizes C4-exo Hyp in a stereoselective fashion. Co-crystal structures and electrostatic potential calculations support and rationalize the observed preferential recognition for (3R,4S)-F-Hyp over the corresponding (3S,4S) epimer by VHL. We show that (3R,4S)-F-Hyp provides bioisosteric Hyp substitution in both hypoxia-inducible factor 1 alpha (HIF-1α) substrate peptides and peptidomimetic ligands that form part of PROTAC (proteolysis targeting chimera) conjugates for targeted protein degradation. Despite a weakened affinity, Hyp substitution with (3S,4S)-F-Hyp within the PROTAC MZ1 led to Brd4-selective cellular degradation at concentrations >100-fold lower than the binary K d for VHL. We anticipate that the disclosed chemistry of 3-fluoro-4-hydroxyprolines and their application as VHL ligands for targeted protein degradation will be of wide interest to medicinal organic chemists, chemical biologists, and drug discoverers alike.
Cooperativity is an important parameter to understand the ternary complexes formed by protein degraders. We developed fluorine NMR competition binding experiments to determine cooperativity of ...PROTACs. We show applicability to estimate both positive and negative cooperativity, also with homo-dimerizers, and highlight key features and considerations for optimal assay development.
In this work we showcase the development of competitive fluorine NMR assays to determine the cooperativities of multiple protein degraders, focusing on key aspects of assay design and comparisons with orthogonal biophysical approaches.
Objective
The aim of this study was to systematically analyze the influence of smoking on the incidence of peri‐implantitis.
Materials and Methods
The search was performed in the National Library of ...Medicine (MEDLINE‐PubMed), SCOPUS, EMBASE, and ISI Web of Science databases (finished on November 30, 2022). Systematic review and meta‐analysis were conducted according to PRISMA statement. Prospective cohort studies that evaluate the incidence of peri‐implantitis in smokers and non‐smokers were included. Two authors independently searched for eligible studies, screened titles, and s, did the full‐text analysis, extracted data, and performed the risk‐of‐bias assessment. The results were summarized through random‐effects meta‐analyses. The GRADE method was used to determine the certainty of evidence.
Results
A total of 7 studies with 702 patients and 1959 implants were included for analysis. The meta‐analysis revealed a significant difference between smokers and non‐smokers for the risk of peri‐implantitis in the implant‐based (p < .0001) and patient‐based analysis (p = .003). A strong association between smoking and the risk for peri‐implantitis was verified at the implant level (RR: 2.04, 95% CI: 1.46–1.85) and the patient level (RR: 2.79, 95% CI: 1.42–5.50).
Conclusions
Moderate certainty evidence suggests that smoking is associated with peri‐implantitis compared to non‐smoking at the patient and implant levels.
Objectives
This review aimed to assess the impact of mouthwashes on the composition of the human oral microbiome.
Method
An electronic search algorithm was adapted to MEDLINE‐PubMed, Scopus, Embase ...and ISI Web of Science, and reference lists of relevant sources were manually searched. Inclusion criteria were controlled clinical trials published in English whose population were adult individuals who rinse with antimicrobial mouthwashes and that analysed changes in the oral microbiome by metataxonomy, metagenomics or phylogenetic microarray. Identified studies were screened and assessed following the PRISMA guidelines, and results were compiled into qualitative synthesis of the evidence.
Results
Five controlled clinical studies were included. These studies found associations between the daily use of mouthwashes and changes in the oral microbiome, but the nature of the effect varied according to the mouthwash. Chlorhexidine (CHX) rinses lowered microbial diversity. While 7‐day use of CHX led to increases in the abundance of Neisseria, Streptococcus and Granulicatella and a decrease in the abundance of Actinomyces, its prolonged use led to widespread reductions in several genera and species. Cetylpyridinium chloride‐containing mouthwashes specifically lowered the abundance of gingivitis‐associated genera. In contrast, N‐acetyl cysteine‐based mouthwashes did not promote changes in the oral microbiome.
Conclusions
Despite substantial heterogeneity, we found evidence to support the hypothesis that CHX and CPC mouthwashes promote changes in oral microbial structure and/or reductions in community diversity that favour the resolution of dysbiosis. However, future large population‐based studies of adequate duration are needed to fully understand the extent to which antimicrobial mouthwashes modulate the microbiome.
Correction for ‘Estimating the cooperativity of PROTAC-induced ternary complexes using
19
F NMR displacement assay’ by Guilherme Vieira de Castro
et al., RSC Med. Chem.
, 2021,
12
, 1765–1770, DOI:
...10.1039/D1MD00215E
.
Objective
To analyze bibliometrics, characteristics, and the risk of bias of randomized controlled trials (RCTs) on dental implants published in six high‐impact factor journals and to identify ...factors contributing to citation number.
Materials and Methods
A systematic electronic search was conducted in four databases (PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials) to identify RCTs on dental implants published in six dental journals between 2016 and 2017. Twenty‐five bibliometric variables and paper characteristics were extracted to evaluate their contribution to the citation count. Risk of bias analysis was performed using the RoB2 tool. Negative binomial regression was used to examine the effects of predictor variables on the Citation count. Significance level was set to 5%.
Results
A total of 150 RCTs included received a cumulative citation count of 3452 until July 2022. In the negative binomial regression analysis, open‐access RCTs exhibited 60% more citations, and RCTs that presented statistical significance received 46% more citations. Conversely, first author affiliations from Africa, Asia and Oceania continents showed 49% fewer citations than publications from Europe. Regarding the risk of bias, 73.3% of the RCTs had some concerns, while 26% were deemed to have a high risk of bias. Only one RCT (0.07%) showed a low risk of bias.
Conclusion
Within the limitation of the study, factors such as open access, statistically significant results, and country influence the number of citations received by the RCTs on dental implants.
Aim
To investigate if there was an association between genetic polymorphisms in tumour necrosis factor (TNF)‐⍺ and its receptors TNFRSF1A and TNFRSF1B with persistent apical periodontitis (PAP) in ...Brazilian subjects.
Methodology
Patients who had pulpal necrosis and apical periodontitis at the time of treatment, with at least 1‐year of follow‐up after non‐surgical root canal treatment were recalled. Three hundred and seventy eight subjects were included, 150 subjects with signs/symptoms of PAP and 228 subjects with root canal‐treated teeth exhibiting healthy perirradicular tissues (healed). Genomic DNA was extracted from saliva and used for TNF‐⍺ (rs1800629), TNFRSF1A (rs1800693) and TNFRSF1B (rs1061622) genotyping by real‐time PCR. Genotypes and alleles frequencies were evaluated by c2 or Fisher's exact tests and odds ratios were implemented (α = 5%).
Results
The genetic polymorphism in TNF‐α (rs1800629) was associated as a protective factor for the development of PAP (p < .05), once subjects who presented at least one allele A (AA+AG X GG), had a higher chance to lesion repair (p < .05). The polymorphisms rs1800693 and rs1061622 in TNF receptors (TNFRSF1A and TNFRSF1B, respectively) were not associated with the development of PAP (p > .05).
Conclusions
The observed results demonstrate that polymorphism in TNF‐α but not in its receptors is associated with PAP.
In this work, three novel catalysts were prepared by 2.5, 5.0, and 10.0 wt.% facile impregnation with an iron and molybdenum mixed oxide (Fe/Mo) on an aluminum pillared clay (Al-PILC) support. These ...materials were characterized by scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS), X-ray diffraction (XRD), temperature programed reduction (TPR), and nitrogen (N
2
) physisorption at 77 K. Characterizations indicated that the metal particles were dispersed on the surface of the three catalysts, and the interlayer d
001
spacing of the pillared material remained unchanged after the impregnation process. The catalytic tests showed good results for DBT oxidation using the synthesized catalysts, with high turnover frequency (TOF) values, particularly for the material with 5.0 wt.% Fe/Mo. Theoretical calculations were carried out at the density functional theory (DFT) level, to investigate how the DBT molecules were adsorbed onto the surface of the mixed oxide. The lowest energy proposal was obtained when both Fe and Mo were present at the active sites, indicating a possible synergistic effect of the metals on catalyst activity. Reuse tests indicated that the catalysts could be employed effectively for up to 3 cycles in a row, then a decrease in activity occurred and the active sites needed to be regenerated.
In the search for novel antimicrobial therapeutics, toxin-antitoxin (TA) modules are promising yet underexplored targets for overcoming antibiotic failure. The bacterial toxin Doc has been associated ...with the persistence of Salmonella in macrophages, enabling its survival upon antibiotic exposure. After developing a novel method to produce the recombinant toxin, we have used antitoxin-mimicking peptides to thoroughly investigate the mechanism by which its cognate antitoxin Phd neutralizes the activity of Doc. We reveal insights into the molecular detail of the Phd–Doc relationship and discriminate antitoxin residues that stabilize the TA complex from those essential for inhibiting the activity of the toxin. Coexpression of Doc and antitoxin peptides in Salmonella was able to counteract the activity of the toxin, confirming our in vitro results with equivalent sequences. Our findings provide key principles for the development of chemical tools to study and therapeutically interrogate this important class of protein–protein interactions.
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