2,5-diketopiperazines (DKPs) are cyclic dipeptides ubiquitously found in nature. In particular, cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) are frequently detected in many microbial cultures. Each of these DKPs has four possible stereoisomers due to the presence of two chirality centers. However, absolute configurations of natural DKPs are often ambiguous due to the lack of a simple, sensitive, and reproducible method for stereochemical assignment. This is an important problem because stereochemistry is a key determinant of biological activity. Here, we report a synthetic DKP library containing all stereoisomers of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro). The library was subjected to spectroscopic characterization using mass spectrometry, NMR, and electronic circular dichroism (ECD). It turned out that ECD can clearly differentiate DKP stereoisomers. Thus, our ECD dataset can serve as a reference for unambiguous stereochemical assignment of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) samples from natural sources. The DKP library was also subjected to a biological screening using assays for E. coli growth and biofilm formation, which revealed distinct biological effects of cyclo(D-Phe-L-Pro).
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Structural Identification, Synthesis and Biological Activity of Two Volatile Cyclic Dipeptides in a Terrestrial Vertebrate
Single substances within complex vertebrate chemical signals could be physiologically or behaviourally active. However, the vast diversity in chemical structure, physical properties and molecular size of semiochemicals makes identifying pheromonally active compounds no easy task. Here, we identified two volatile cyclic dipeptides, cyclo(L-Leu-L-Pro) and cyclo(L-Pro-L-Pro), from the complex mixture of a chemical signal in terrestrial vertebrates (lizard genus
- Award ID(s):
- 1665356
- NSF-PAR ID:
- 10154408
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 10
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract As COVID‐19 infection caused severe public health concerns recently, the development of novel antivirals has become the need of the hour. Main protease (Mpro) has been an attractive target for antiviral drugs since it plays a vital role in polyprotein processing and virus maturation. Herein we report the discovery of a novel class of inhibitors against the SARS‐CoV‐2, bearing histidine
α ‐nitrile motif embedded on a simple dipeptide framework.In‐vitro andin‐silico studies revealed that the histidineα ‐nitrile motif envisioned to target the Mprocontributes to the inhibitory activity. Among a series of dipeptides synthesized featuring this novel structural motif, some dipeptides displayed strong viral reduction (EC50=0.48 μM) with a high selectivity index, SI>454.54. These compounds also exhibit strong binding energies in the range of −28.7 to −34.2 Kcal/mol. The simple dipeptide structural framework, amenable to quick structural variations, coupled with ease of synthesis from readily available commercial starting materials are the major attractive features of this novel class of SARS‐CoV‐2 inhibitors. The histidineα ‐nitrile dipeptides raise the hope of discovering potent drug candidates based on this motif to fight the dreaded SARS‐CoV‐2. -
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Rationale The function of a protein or the binding affinity of an antibody can be substantially altered by the replacement of leucine (Leu) with isoleucine (Ile), and vice versa, so the ability to identify the correct isomer using mass spectrometry can help resolve important biological questions. Tandem mass spectrometry approaches for Leu/Ile (Xle) discrimination have been developed, but they all have certain limitations.
Methods Four model peptides and two wild‐type peptide sequences containing either Leu or Ile residues were subjected to charge transfer dissociation (CTD) mass spectrometry on a modified three‐dimensional ion trap. The peptides were analyzed in both the 1+ and 2+ charge states, and the results were compared to conventional collision‐induced dissociation spectra of the same peptides obtained using the same instrument.
Results CTD resulted in 100% sequence coverage for each of the studied peptides and provided a variety of side‐chain cleavages, including
d ,w andv ions. Using CTD, reliabled andw ions of Xle residues were observed more than 80% of the time. When present,d ions are typically greater than 10% of the abundance of the correspondinga ions from which they derive, andw ions are typically more abundant than thez ions from which they derive.Conclusions CTD has the benefit of being applicable to both 1+ and 2+ precursor ions, and the overall performance is comparable to that of other high‐energy activation techniques like hot electron capture dissociation and UV photodissociation. CTD does not require chemical modifications of the precursor peptides, nor does it require additional levels of isolation and fragmentation.
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Abstract Background Microbial co-cultures and consortia are of interest in cell-based molecular production and even as “smart” therapeutics in that one can take advantage of division of labor and specialization to expand both the range of available functions and mechanisms for control. The development of tools that enable coordination and modulation of consortia will be crucial for future application of multi-population cultures. In particular, these systems would benefit from an expanded toolset that enables orthogonal inter-strain communication.
Results We created a co-culture for the synthesis of a redox-active phenazine signaling molecule, pyocyanin (PYO), by dividing its synthesis into the generation of its intermediate, phenazine carboxylic acid (PCA) from the first strain, followed by consumption of PCA and generation of PYO in a second strain. Interestingly, both PCA and PYO can be used to actuate gene expression in cells engineered with the
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Abstract BACKGROUND Azoles are an important class of compounds that are widely used as corrosion inhibitors in aircraft de‐icing agents, cooling towers, semiconductor manufacturing and household dishwashing detergents. They also are important moieties in pharmaceutical drugs and fungicides. Azoles are widespread emerging contaminants occurring frequently in water bodies. Azole compounds can potentially cause inhibition towards key biological processes in natural ecosystems and wastewater treatment processes. Of particular concern is the inhibition of azoles to the nitrification process (aerobic oxidation of ammonium). This study investigated the acute toxicity of azole compounds towards the anaerobic ammonia oxidation (anammox) process, which is an important environmental biotechnology gaining traction for nutrient‐nitrogen removal during wastewater treatment. In this study, using batch bioassay techniques, the anammox toxicity of eight commonly occurring azole compounds was evaluated.
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H ‐benzotriazole and 5‐methyl‐1H ‐benzotriazole had the highest inhibitory effect on the anammox process, causing 50% decrease in anammox activity (IC50) at concentrations of 19.6 and 17.8 mg L−1, respectively. 1H‐ imidazole caused less severe toxicity with an IC50of 79.4 mg L−1. The other azole compounds were either nontoxic (1H‐ pyrazole, 1H‐ 1,2,4‐triazole and 1‐methyl‐pyrazole) or at best mildly toxic (1H‐ benzotriazole‐5‐carboxylic acid and 3,5‐dimethyl‐1H‐ pyrazole) towards the anammox bacteria at the concentrations tested.CONCLUSIONS This study showed that most azole compounds tested displayed mild to low or no toxicity towards the anammox bacteria. The anammox bacteria were found to be far less sensitive to azoles compared to nitrifying bacteria. © 2019 Society of Chemical Industry
