A comprehensive study of Chuanwang Xiaoyan capsule based on characterization of chemical constituents in vitro and in vivo using ultra‐high‐performance liquid chromatography‐quadrupole‐Exactive Orbitrap mass spectrometry and pharmacokinetic study of multiple components in rats using ultra‐high‐performance liquid chromatography‐triple quadrupole‐tandem mass spectrometry

Article

Author: Wang, Yufeng ; Yu, Jia ; Wei, Lan ; Wang, Hongjin ; Gao, Aichun

AbstractChuanwang Xiaoyan (CWXY) capsule is primarily used to treat a variety of acute and chronic inflammations, including acute and chronic pharyngitis and tonsillitis. However, a systematic study of its chemical constituents is still not available. This study evaluated the chemical constituents in vitro and metabolite profiles in vivo of CWXY using ultra‐high‐performance liquid chromatography (UHPLC) coupled with Q‐Exactive Orbitrap mass spectrometry, and the pharmacokinetic behaviors of the nine main components in rats were detected using ultra‐high‐performance liquid chromatography‐triple quadrupole‐mass spectrometry (UPLC‐QQQ‐MS/MS). A total of 92 chemical constituents in CWXY were preliminarily identified in vitro. After oral administration to rats, 56 prototype components and 128 metabolites of CWXY were detected in the biological samples of rat plasma, urine, bile, and feces. Of these prototype components and metabolites, seven new compounds, namely M15, M16, M25, M30, M31, M71, and M128, were detected for the first time. The quantitation method of nine components in rat plasma was developed using a pharmacokinetic study. To the best of our knowledge, this study was the first to investigate the pharmacokinetic behavior of triumbelletin.

01 Sep 2019·Biotechnology and Bioengineering

Rational surface engineering of an arginine deiminase (an antitumor enzyme) for increased PEGylation efficiency

Article

Author: Schwaneberg, Ulrich ; Yang, Jianhua ; Zhu, Leilei ; Cheng, Feng

AbstractArginine deiminase (ADI) is a therapeutic protein for cancer therapy of arginine‐auxotrophic tumors. However, its application as anticancer drug is hampered by its poor stability under physiological conditions in the bloodstream. Commonly, random PEGylation is being used for increasing the stability of ADI and in turn the improved half‐life. However, the traditional random PEGylation usually leads to poor PEGylation efficiency due to the limited number of Lys on the protein surface. To boost the PEGylation efficiency and enhance the stability of ADI further, surface engineering of PpADI (an ADI from Pseudomonas plecoglossicida) to increase the suitable PEGylation sites was carried out. A new in silico approach for increasing the PEGylation sites was developed. The validation of this approach was performed on previously identified PpADI variant M31 to increase potential PEGylation sites. Four Arg residues on the surface of PpADI M31 were selected through three criteria and subsequently substituted to Lys, aiming for providing primary amines for PEGylation. Two out of the four substitutions (R299K and R382K) enhanced the stability of PEGylated PpADI in human serum. The average numbers of PEGylation sites were increased from ~12 (tetrameric PpADI M31, starting point) to ~20 (tetrameric PpADI M36, final variant). Importantly, the PEGylated PpADI M36 after PEGylation exhibited significantly improved Tm values (M31: 40°C; M36: 40°C; polyethylene glycol [PEG]‐M31: 54°C; PEG‐M36: 64°C) and half‐life in human serum (M31: 1.9 days; M36: 2.0 days; PEG‐M31: 3.2 days; PEG‐M36: 4.8 days). These proved that surface engineering is an effective approach to increase the PEGylation efficiency which therefore enhances the stability of therapeutic enzymes. Furthermore, the PEGylated PpADI M36 represents a highly attractive candidate for the treatment of arginine‐auxotrophic tumors.

17 Jul 2015·ACS Synthetic BiologyQ2 · BIOLOGY

A Competitive Flow Cytometry Screening System for Directed Evolution of Therapeutic Enzyme

Q2 · BIOLOGY

Letter

Author: Zhu, Leilei ; Shehzad, Aamir ; Schwaneberg, Ulrich ; Pitzler, Christian ; Bernhagen, Jürgen ; Cheng, Feng ; Lue, Hongqi ; Kardashliev, Tsvetan

A ligand-mediated eGFP-expression system (LiMEx) was developed as a novel flow cytometry based screening platform that relies on a competitive conversion/binding of arginine between arginine deiminase and arginine repressor. Unlike product-driven detection systems, the competitive screening platform allows to evolve enzymes toward efficient operation at low substrate concentrations under physiological conditions. The principle of LiMEx was validated by evolving arginine deiminase (ADI, an anticancer therapeutic) for stronger inhibition of tumor growth. After screening of ∼8.2 × 10(6) clones in three iterative rounds of epPCR libraries, PpADI (ADI from Pseudomonas plecoglossicida) variant M31 with reduced S0.5 value (0.17 mM compared to 1.23 mM (WT)) and, importantly, increased activity at physiological arginine concentration (M31:6.14 s(-1); WT: not detectable) was identified. Moreover, M31 showed a significant inhibitory effect against SK-MEL-28 and G361 melanoma cell lines. (IC50 = 0.02 μg/mL for SK-MEL-28 and G361).

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Indication	Highest Phase	Country/Location	Organization	Date
Leukodystrophy, Globoid Cell	Phase 1	US	M6P TherapeuticsStartup	-

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