Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and bio-functional diversity. DKPs, especially those containing proline, due to their unique features such as, inter alia, extra-rigid conformation, high resistance to enzyme degradation, increased cell permeability, and expandable ability to bind a diverse of targets with better affinity, have emerged in the last years as biologically pre-validated platforms for the drug discovery. Recent advances have revealed their enormous potential in the development of next-generation theranostics, smart delivery systems, and biomaterials. Here, we present an updated review on the biological and structural profile of these appealing biomolecules, with a particular emphasis on those with anticancer properties, since cancers are the main cause of death all over the world. Additionally, we provide a consideration on supramolecular structuring and synthons, based on the proline-based DKP privileged scaffold, for inspiration in the design of compound libraries in search of ideal ligands, innovative self-assembled nanomaterials, and bio-functional architectures.
Noncoding small RNAs (sRNAs) act in conjunction with the RNA chaperone Hfq to regulate gene expression in bacteria. Because Hfq is required for virulence in several bacterial pathogens, the Hfq-sRNA system is an attractive target for antibiotic development. A reporter strain in which the expression of yellow fluorescent protein (YFP) is controlled by Hfq-sRNA was engineered to identify inhibitors of this system. A reporter that is targeted by Hfq in conjunction with the RybB sRNA was used in a genetic screen to identify inhibitors from a library of cyclic peptides produced in Escherichia coli using split-intein circular ligation of peptides and proteins (SICLOPPS), an intein-based technology. One cyclic peptide identified in this screen, RI20, inhibited Hfqmediated repression of gene expression in conjunction with both RybB and an unrelated sRNA, MicF. Gel mobility shift assays showed that RI20 inhibited binding of Hfq to RybB and MicF with similar K i values. These data suggest that RI20 inhibits Hfq activity by blocking interactions with sRNAs and provide a paradigm for inhibiting virulence genes in Gram-negative pathogens.
Gram-negative bacteria are formidable pathogens because their cell envelope presents an adaptable barrier to environmental and host-mediated challenges. The stress response pathway controlled by the alternative sigma factor E is critical for maintenance of the cell envelope. Because E is required for the virulence or viability of several Gram-negative pathogens, it might be a useful target for antibiotic development. To determine if small molecules can inhibit the E pathway, and to permit highthroughput screening for antibiotic lead compounds, a E activity assay that is compatible with high-throughput screening was developed and validated. The screen employs a biological assay with positive readout. An Escherichia coli strain was engineered to express yellow fluorescent protein (YFP) under negative regulation by the E pathway, such that inhibitors of the pathway increase the production of YFP. To validate the screen, the reporter strain was used to identify E pathway inhibitors from a library of cyclic peptides. Biochemical characterization of one of the inhibitory cyclic peptides showed that it binds E , inhibits RNA polymerase holoenzyme formation, and inhibits E -dependent transcription in vitro. These results demonstrate that alternative sigma factors can be inhibited by small molecules and enable high-throughput screening for inhibitors of the E pathway. Gram-negative bacteria are remarkably successful pathogens, and the increasing prevalence of antibiotic resistance in these species presents a significant threat to human health (1, 2). A major factor contributing to the success of these bacteria in virulence and in evading antibiotic action is their ability to maintain the integrity of the outer compartment of the cell, the cell envelope, which consists of the outer membrane, the periplasmic space, the peptidoglycan layer, and the cytoplasmic membrane. The E pathway is one of the key regulatory systems used by Gram-negative bacteria to adapt to challenges to the cell envelope encountered in the environment, including those presented by the host during infection (3, 4).Sigma factors, such as E , are the subunits of RNA polymerase (RNAP) responsible for promoter recognition and transcription initiation (5, 6). The majority of transcription in the cell is directed by the housekeeping sigma factor, 70 . However, most bacteria also possess a series of alternative sigma factors that are activated by particular stresses and redirect RNAP to promoters for genes required to respond to the stress in question (6, 7).E is a member of the largest and most widespread group of alternative sigma factors, referred to as the group 4 or ECF (extracytoplasmic function) sigma factors (8, 9). ECF sigma factors have been implicated in stress survival, virulence, and antibiotic resistance in many pathogens (3,4,10,11). rpoE, the gene encoding E , is essential for viability of Escherichia coli K-12 and Yersinia enterocolitica (12-16). rpoE is also likely required for viability in adherent-invasive E. coli (associated with Crohn's ...
The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]4 and c[WR]5 consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in the solution and conjugated with each other through an amide bond to afford the tricyclic peptide, which demonstrated modest antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli (E. coli) with a minimum inhibitory concentration (MIC) of 64–128 µg/mL. The tricyclic peptide was found to be nontoxic up to 30 µM in the breast cancer cell lines (MDA-MB-231). The presence of tricyclic peptide enhanced cellular uptakes of fluorescently-labeled phosphopeptide (F’-GpYEEI, 18-fold), anti-HIV drugs (lamivudine (F’-3TC), emtricitabine (F’-FTC), and stavudine (F’-d4T), 1.7–12-fold), and siRNA (3.3-fold) in the MDA-MB-231 cell lines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.