Diversity-Oriented Biosynthesis Yields l-Kynurenine Derivative-Based Neurological Drug Candidate Collection.

Natural product libraries with a remarkable range of biological activities play pivotal roles in drug discoveries due to their extraordinary structural complexity and immense diversity. l-Kynurenine (l-Kyn)-based derivatives are privileged pharmacophores that exhibit diverse therapeutic implications in neurological disorders. However, the difficulty in obtaining l-Kyn analogues with different skeletal structures has recently led to a decline in its medicinal research. Herein, we report a two-step, one-pot protocol for diversity-oriented biosynthesis of a collection of previously intractable l-Kyn-like compounds. The success of these challenging transformations mainly depends on unlocking the new catalytic scope of tryptophan 2,3-dioxygenases, followed by rational site-directed mutagenesis to modify the substrate domains further. As a result, 18 kynurenine analogues with diverse molecular scaffolds can be rapidly assembled in a predictable manner with 20-83% isolated yields, which not only fill the voids of the catalytic profile of tryptophan 2,3-dioxygenases with an array of substituent groups (e.g., F, Cl, Br, I, CH3, OCH3, and NO2) but also update the current understanding of its substrate spectrum. Our work highlights the great potential of existing enzymes in addressing long-standing synthetic challenges for facilitating the development or discovery of new drug candidates. Furthermore, our approach enables translating the reaction parameters from Eppendorf tubes to 1 L scale, affording l-4-Cl-Kyn and l-5-Cl-Kyn both on a gram scale with more than 80% isolated yields, and provides a promising alternative to further industrial applications.

A dual-signal self-checking photoelectrochemical immunosensor based on the sole composite of MIL-101(Cr) and CdSe quantum dots for the detection of α-fetoprotein.

Designing a photoelectrochemical (PEC) immunosensor that can produce dual photocurrent signals which can refer to each other is a great importance but a big challenge. In this manuscript, a novel dual photocurrent signals immunosensor was constructed for the detection of α-fetoprotein (AFP). Unlike the usual method of using two composite materials to provide cathode and anode photocurrent respectively, this work applies only one compound of MIL-101 (Cr) and CdSe quantum dots (QDs). Thereinto, we found that the photocurrent polarity of MIL-101(Cr) would switch by adjusting applied voltage. And then CdSe QDs was introduced by simple ultrasound mixing to boost the dual photocurrent signals. Furthermore, in the composite of M&C, the electron transfer path between MIL-101(Cr) and CdSe QDs may switch between "Z-type" and "Ⅱ-type" by adjusting voltage. Benefiting by the dual signals, the proposed sensor can not only perform sensitively quantitative detection of α-fetoprotein (AFP), but also can intuitively estimate the accuracy and reliability of the test result by determining whether the corresponding relationship of "cathode photocurrent-analyte concentration-anode photocurrent" is established. The linear ranges of the sensing electrodes as cathode and anode are the same, both from 0.1 to 300 ng mL-1. The limit of detection (LOD) is 0.082 ng mL-1 (S/N = 3) when it used as an anode, and the LOD is 0.054 ng mL-1 (S/N = 3) when it served as cathode. Furthermore, this sensor showed acceptable stability, reproducibility, specificity, and feasibility of detecting AFP in human serum, which has broad development prospects in the early clinical diagnosis.

Photoelectrochemical immunosensor based on CdSe@BiVO4 Co-sensitized TiO2 for carcinoembryonic antigen.

The fast and accurate detection of Carcinoembryonic Antigen (CEA) plays an important role in clinical cancer treatment and therapy. An ultrasensitive photoelectrochemical (PEC) immunosensor for the detection of CEA was constructed using CdSe@BiVO4 co-sensitized TiO2 nanorods as photoactive materials. TiO2 nanorods were assembled on the FTO modified electrode to immobilize capture antibodies. With a sandwich immunoassay format, CEA and signal antibodies labelled CdSe@BiVO4 were introduced in sequence via specific immunoreaction, and the ultrahigh sensitivity of this immunoassay results from the following three aspects. Firstly, the co-sensitization of BiVO4 and CdSe extends the absorption range of TiO2 from ultraviolet region to visible light region, which can adequately utilize the light energy; Secondly, the effective matching of energy levels among TiO2, CdSe and BiVO4 accelerates the separation and transfer of photogenerated electron-hole pairs and significantly improves the PEC performance; Finally, the introduced Au evidently expedites the interfacial electron transfer from TiO2 to FTO electrode, further resulting in noticeably increased photocurrent. Based on multiple signal amplification strategy, a largely linear detection range from 0.01 ng mL-1 to 50 ng mL-1 with a low detection limit (0.5 pg mL-1) were obtained. In addition, the prepared immunosensor with attractive properties provides a promising platform for PEC detection.