Optimised Synthesis of the Bacterial Magic Spot (p)ppGpp Chemosensor PyDPA

Conti, Giovanni Maria; Minneci, Marco; Sattin, Sara

doi:10.1002/cbic.201900013

Cited by 6 publications

(6 citation statements)

References 24 publications

(27 reference statements)

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“…Traditional methods of detecting (p)ppGpp rely on radiolabeling (p)ppGpp with 32 P and measuring with thin layer chromatography [11–13] or high‐performance liquid chromatography [14, 15] . Some colorimetric and fluorescent probes have also been developed recently [16–21] . These chemosensors enable the detection of (p)ppGpp in vitro or from cell extracts, however, not in individual living cells.…”

Section: Figurementioning

confidence: 99%

Live‐Cell Imaging of Guanosine Tetra‐ and Pentaphosphate (p)ppGpp with RNA‐based Fluorescent Sensors**

Sun

Zhao

et al. 2021

Angew Chem Int Ed

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Guanosine tetra-and pentaphosphate, (p)ppGpp, are important alarmone nucleotides that regulate bacterial survival in stressful environment. A direct detection of (p)ppGpp in living cells is critical for our understanding of the mechanism of bacterial stringent response. However, it is still challenging to image cellular (p)ppGpp. Here, we report RNA-based fluorescent sensors for the live-cell imaging of (p)ppGpp. Our sensors are engineered by conjugating a recently identified (p)ppGpp-specific riboswitch with a fluorogenic RNA aptamer, Broccoli. These sensors can be genetically encoded and enable direct monitoring of cellular (p)ppGpp accumulation. Unprecedented information on cellto-cell variation and cellular dynamics of (p)ppGpp levels is now obtained under different nutritional conditions. These RNA-based sensors can be broadly adapted to study bacterial stringent response.

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Section: Figurementioning

confidence: 99%

Live‐Cell Imaging of Guanosine Tetra‐ and Pentaphosphate (p)ppGpp with RNA‐based Fluorescent Sensors**

Sun

Zhao

et al. 2021

Angew Chem Int Ed

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“…In this framework, we optimized the synthesis of a fluorescent (p)ppGpp selective chemosensor [ 35 ], and here, we report the identification of three novel chemical scaffolds for the design of selective RSH inhibitors through fragments virtual screening campaigns followed by experimental validation of representative fragments on the synthetase site of the “long” RSH protein Rel Seq ( S. equisimilis ).…”

Section: Introductionmentioning

confidence: 99%

New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds

et al. 2022

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Antimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bacterial bet-hedging strategy, will lead to new molecular entities displaying low selective pressure, thereby reducing the insurgence of AMR. Here, we describe a way to target (p)ppGpp (guanosine tetra- or penta-phosphate) signaling, a non-essential pathway involved in the formation of persisters, with a structure-based approach. A superfamily of enzymes called RSH (RelA/SpoT Homolog) regulates the intracellular levels of this alarmone. We virtually screened several fragment libraries against the (p)ppGpp synthetase domain of our RSH chosen model RelSeq, selected three main chemotypes, and measured their interaction with RelSeq by thermal shift assay and STD-NMR. Most of the tested fragments are selective for the synthetase domain, allowing us to select the aminobenzoic acid scaffold as a hit for lead development.

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“…The eptide-nucleoside Relacin [127,128] and its analogues have been the first example of a tailored approach against a specific bacterial target (Rel proteins) [129] that unfortunately showed limited activities and cell penetrating properties. In this regard, we have been active in the targeting of Rel proteins with a structure-based approach [130][131][132] that led to interesting amino acid-derived compounds. www.videleaf.com In 2019, the synthesis of vancomycin analogues with the addition of single amino acid residues was reported demonstrating that only one arginine, V-r, led to significantly improved efficacy against gram-positive bacteria, including MRSA [133].…”

Section: Cell-penetrating Peptidesmentioning

confidence: 99%

nature inspired and medicinally relevant short peptides

Ciulla,

Civera,

Sattin

2023

Updates in Pharmacology

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Peptides constitute an important component of Nature's pharmacy and they play a significant role in several signaling pathways acting as natural biological messengers. While nature has mastered the cycle of creation, application, and destruction of large and short peptides to the benefit of the host organism, organic and medicinal chemists have in their capacity and small steps, made big developments in the field of peptide synthesis as well as in developing them as therapeutics. In comparison to their big counterparts, i.e. proteins, short peptides encompass several advantages, from the ease of synthesis to their physicochemical properties. However, the real challenge for in vivo application of therapeutic peptides is to overcome their low plasma availability and their fast enzymatic degradation. This review briefly covers the relevant areas of medicinally important short peptides and the recent developments made to turn these peptides into therapeutics. Also presented in this article are important efforts and strategies used to overcome some of the inherent limitations of peptidic molecules and thereby facilitate their progression in the clinical phases towards approved drugs.

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Optimised Synthesis of the Bacterial Magic Spot (p)ppGpp Chemosensor PyDPA

Cited by 6 publications

References 24 publications

Live‐Cell Imaging of Guanosine Tetra‐ and Pentaphosphate (p)ppGpp with RNA‐based Fluorescent Sensors**

Live‐Cell Imaging of Guanosine Tetra‐ and Pentaphosphate (p)ppGpp with RNA‐based Fluorescent Sensors**

New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds

nature inspired and medicinally relevant short peptides

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