Zhou Lei

Reactive Metabolite-induced Protein Glutathionylation: a Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity

Published date : 13 Jul 2018

Although covalent protein binding is established as the pivotal event underpinning acetaminophen (APAP) toxicity, its mechanistic details remain unclear. In this study, we demonstrated that APAP induces widespread protein glutathionylation in a time-, dose- and bioactivation-dependent manner in HepaRG cells.

type
Journal Paper
journal
Molecular & Cellular Proteomics, 2018, Jul 13, doi: 10.1074/mcp.RA118.000875
Impact Factor
5.232

A novel fragment based strategy for membrane active antimicrobials against MRSA

Published date : 05 Jan 2015

Membrane active antimicrobials are a promising new generation of antibiotics that hold the potential to avert antibiotic resistance. However, poor understanding of the action mechanism and the lack of general design principles have impeded their development. Here we extend the concept of fragment based drug design and propose a pharmacophore model based on first principles for the design of membrane active antimicrobials against Gram positive pathogens.

type
Journal Paper
journal
Biochimica et Biophysica Acta, 2015 Jan 10;1848(4):1023-1031. doi: 10.1016/j.bbamem.2015.01.001

Amino Acid-Modified Xanthone Derivatives: Novel, Highly Promising Membrane-active Antimicrobials for Multidrug-resistant Gram-positive Bacterial Infections

Published date : 04 Dec 2014

Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials.

type
Journal Paper
journal
Journal of Medicinal Chemistry, 2014, Dec 4

Design and Synthesis of Amphiphilic Xanthone-Based, Membrane-Targeting Antimicrobials with Improved Membrane Selectivity

Published date : 13 Feb 2013

This work describes how to tune the amphiphilic conformation of α-mangostin, a natural compound that contains a hydrophobic xanthone scaffold, to improve its antimicrobial activity and selectivity for Gram-positive bacteria. A series of xanthone derivatives was obtained by cationic modification of the free C3 and C6 hydroxyl groups of α-mangostin with amine groups of different pKa values. Modified structures using moieties with high pKa values, such as AM-0016 (3b), exhibited potent antimicrobial properties against Gram-positive bacteria.

type
Journal Paper
journal
Journal of Medicinal Chemistry March 2013, doi : 10.1021/jm301683j
Impact Factor
5.248

Molecular dynamics simulations of a new branched antimicrobial peptide: A comparison of force fields

Published date : 04 Dec 2012

Branched antimicrobial peptides are promising as a new class of antibiotics displaying high activity and low toxicity and appear to work through a unique mechanism of action. We explore the structural dynamics of a covalently branched 18 amino acid peptide (referred to as B2088) in aqueous and membrane mimicking environments through molecular dynamics (MD) simulations. Towards this, we carry out conventional MD simulations and supplement these with replica exchange simulations.

type
Journal Paper
journal
Journal of Chemical Physics 2012, Dec 7;137(21):215101. doi: 10.1063/1.4768899
Impact Factor
3.333

Structure-dependent Charge Density as a Determinant of Antimicrobial Activity of Peptide Analogues of Defensin

Published date : 16 Jul 2009

Defensins are small (3-5 kDa) cysteine-rich cationic proteins found in both vertebrates and invertebrates constituting the front line of host innate immunity. Despite intensive research, bactericidal and cytotoxic mechanisms of defensins are still largely unknown. Moreover, we recently demonstrated that small peptides derived from defensins are even more potent bactericidal agents with less toxicity toward host cells. In this paper, structures of three C-terminal (R36-K45) analogues of human beta-defensin-3 were studied by 1H NMR spectroscopy and extensive molecular dynamics simulations.

type
Journal Paper
journal
Biochemistry, July 11, 2009, 48 (30), pp 7229-7239, DOI: 10.1021/bi900670d
Impact Factor
3.379

Effect of Structural Parameters of Peptides on Dimer Formation and Highly Oxidized Side Products in the Oxidation of Thiols of Linear Analogues of Human b-Defensin 3 by Dimethyl Sulfoxide

Published date : 24 Dec 2008

he purpose of this study was to examine the effects of structural parameters of peptides on their oxidation by DMSO, including location of cysteine, effect of adjunct group participation, molecular hydrophobicity, steric hindrance or the accessibility of thiol group and peptide conformation, on oxidation rates, dimer formation and associated side products.

type
Book/Book Chapter
journal
Journal of Peptide Science, DOI: 10.1002/psc.1100
Impact Factor
1.807

Effect of Structural Parameters of Peptides on Dimer Formation and Highly Oxidized Side Products in the Oxidation of Thiols of Linear Analogues of Human b-Defensin 3 by Dimethyl Sulfoxide

Published date : 24 Dec 2008

he purpose of this study was to examine the effects of structural parameters of peptides on their oxidation by DMSO, including location of cysteine, effect of adjunct group participation, molecular hydrophobicity, steric hindrance or the accessibility of thiol group and peptide conformation, on oxidation rates, dimer formation and associated side products.

type
Journal Paper
journal
Journal of Peptide Science, Vol 15, Issue 2, Pg 95-106, doi: 10.1002/psc.1100
Impact Factor
1.768

Linear Analogs of Human Defensin 3: Concepts for Design of Antimicrobial Peptides with Reduced Cytotoxicity to Mammalian Cells

Published date : 08 Mar 2008

A series of engineered linear analogues [coded as F6, W6, Y6, A6, S6 and C(Acm)6] were modeled, designed, synthesized and structurally characterized by mass spectra, circular dichroism, hydrophobicity analysis and molecular modeling. We have screened antimicrobial activity, hemolysis to rabbit erythrocytes, and cytotoxicity to human conjunctival epithelial cells. No significant hemolytic effect was observed for hBD3 or from five of the six analogues [F6, Y6, A6, S6 and C(Acm)6] over the range of 3-100 microg mL(-1).

type
Journal Paper
journal
ChemBioChem, Vol 9, Issue 6, Apr 2008, Pg 964-973, DOI: 10.1002/cbic.200700560
Impact Factor
3.474