Tianyu Jiang

Quorum sensing inhibitors: a patent review

Introduction: Quorum sensing (QS) is a cell-to-cell communication that regulates gene expression and coordinates their behavior in accordance with the cell population density as a result of discerning molecules termed autoinducers (AIs). The processes that QS governed include biofilm formation, bacterial virulence, antibiotic production, competence, conjugation, swarming motility and sporulation. Three main QS AIs are acyl-homoserine lactones, AI-2 and AI peptides. The attractive study of QS leads to an expansive number of QS inhibitors and approaches interfering with QS appearing. Areas covered: This review summarized the recent QS inhibitor-related patents published from 2009 to 2012. The authors have analyzed these patents and have provided an overview of QS inhibitors and their application. Expert opinion: The main strategies for QS inhibition related to the patents are disruption of the AI synthase, inactivation of the signal molecule, antagonism of the receptor and promotion of immune response to AI. Some of the natural or synthetic QS inhibitors display excellent activity to manipulate bacterial pathogenicity to offer significant potential in clinical therapy. However, more efforts are needed to be conducted to determine this form of communication to guide the development of QS inhibitors. Overall, QS is a suitable target for antimicrobial therapy and QS inhibitors are likely to lead to a renaissance of anti-virulence drugs without tolerance, which is the ultimate goal expected to achieve in this field.

A novel coelenterate luciferin-based luminescent probe for selective and sensitive detection of thiophenols

The first dual bioluminescent and chemiluminescent sensor for detecting highly toxic thiophenols has been developed. Such a probe was designed by using a coelenterazine analogue as the luminophore and dinitrophenyl ether as the recognition moiety. It should be noted that this probe displayed good sensitivity and selectivity toward thiophenols, and has been effectively applied for the quantitative detection of thiophenols in aqueous media and complex biological samples.

Bioluminescent Probe for Detecting Mercury(II) in Living Mice

A novel bioluminescence probe for mercury(II) was obtained on the basis of the distinct deprotection reaction of dithioacetal to decanal, so as to display suitable sensitivity and selectivity toward mercury(II) over other ions with bacterial bioluminescence signal. These experimental results indicated such a probe was a novel promising method for mercury(II) bioluminescence imaging in environmental and life sciences ex vivo and in vivo.

Environment-Sensitive Fluorescent Probe for the Human Ether-a-go-go-Related Gene Potassium Channel

A novel environment-sensitive probe S2 with turn-on switch for Human Ether-a-go-go-Related Gene (hERG) potassium channel was developed herein. After careful evaluation, this fluorescent probe showed high binding affinity with hERG potassium channel with an IC50 value of 41.65 nM and can be well applied to hERG channel imaging or cellular distribution study for hERG channel blockers. Compared with other imaging techniques, such as immunofluorescence and fluorescent protein-based approaches, this method is convenient and affordable, especially since a washing procedure is not needed. Meanwhile, this environment-sensitive turn-on design strategy may provide a good example for the probe development for these targets that have no reactive or catalytic activity.

Discovery of a series of 2-phenylnaphthalenes as firefly luciferase inhibitors

As the most convenient and efficient bioluminescence system, the firefly luciferase/luciferin complex has been widely used in life science research and high-throughput screening (HTS). Nonetheless, the interpretation of firefly luciferase-based assay data is often complicated by the occurrence of “false positives,” in part because firefly luciferase (Fluc) is subject to direct inhibition by HTS compounds that might inadvertently act as inhibitors of its catalytic site. Here we report a series of 2-phenylnaphthalenes as Fluc inhibitors with suitable potency both in vitro and in vivo. Besides, our compound 5 showed significant systemic inhibition in transgenic mice. Enzymatic kinetics study reveals that compound 5 is competitive for substrate aminoluciferin and noncompetitive for the second substrate ATP. Furthermore, compound 5 exhibited good performance as a quenching agent in a dual-luciferase reporter assay. We anticipate that these Fluc inhibitors will contribute to the broader utilization of bioluminescence in life science research while circumventing or at least reducing the number of “false positives”.

Bioluminescence probe for γ-glutamyl transpeptidase detection in vivo

To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model.

Discovery of the First Environment-Sensitive Fluorescent Probe for GPR120 (FFA4) Imaging

GPR120, which is activated by long-chain free fatty acids (FFAs), has been recognized as a new attractive target for the treatment of type 2 diabetes and metabolic disease. The visualization and location of GPR120 in native cells can provide powerful information for guiding the physiological and pathological studies of GPR120. We report herein the first potent fluorescent probes that sensitively detect GPR120. We designed and synthesized a series of novel environment-sensitive probes with suitable fluorescence property, high biological activity on the GPR120, and acceptable cytotoxicity. These fluorescent probes targeting GPR120 are expected to expand the toolkit for further studies on GPR120.

Discovery of New Substrates for LuxAB Bacterial Bioluminescence.

In this article, four novel substrates with long halftime have been designed and synthesized successfully for luxAB bacterial bioluminescence. After in vitro and in vivo biological evaluation, these molecules can emit obvious bioluminescence emission with known bacterial luciferase, thus indicating a new promising approach to developing the bacterial bioluminescent system.

Identification of AI-2 Quorum Sensing Inhibitors in Vibrio harveyi Through Structure-Based Virtual Screening

Quorum sensing (QS) is a cell-to-cell communication system that regulates gene expression as a result of the production and perception of signal molecules called autoinducers (AIs). AI-2 is a QS autoinducer produced by both Gram-negative and Gram-positive bacteria, in which it regulates intraspecies and interspecies communication. The identification of QS inhibitors is considered a promising strategy for the development of anti-virulence drugs with reduced selective pressure for resistance. Here we describe a high-throughput virtual screening approach to identify AI-2 quorum sensing inhibitors on the basis of Vibrio harveyi LuxPQ crystal structure. Seven potent inhibitors with IC50 values in the micromolar range were selected with no effect or low effect on V. harveyi growth rate.