Juan Shi

Bio: Juan Shi is an academic researcher from Chinese Ministry of Education. The author has contributed to research in topics: Peptide & Trifluoroacetic acid. The author has an hindex of 3, co-authored 6 publications receiving 27 citations.

Molecular determinants conferring the stoichiometric-dependent activity of α-conotoxins at the human α9α10 nicotinic acetylcholine receptor subtype

Abstract: α9α10 nicotinic acetylcholine receptors (nAChRs) putatively exist at different stoichiometries. We systematically investigated the molecular determinants of α-conotoxins Vc1.1, RgIA#, and PeIA inhibition at hypothetical stoichiometries of the human α9α10 nAChR. Our results suggest that only Vc1.1 exhibits stoichiometric-dependent inhibition at the α9α10 nAChR. The hydrogen bond between N154 of α9 and D11 of Vc1.1 at the α9(+)-α9(−) interface is responsible for the stoichiometric-dependent potency of Vc1.1.

Enhanced Activity against Multidrug-Resistant Bacteria through Coapplication of an Analogue of Tachyplesin I and an Inhibitor of the QseC/B Signaling Pathway.

Abstract: Tachyplesin I (TPI) is a cationic β-hairpin antimicrobial peptide with broad-spectrum, potent antimicrobial activity. In this study, the all d-amino acid analogue of TPI (TPAD) was synthesized, and its structure and activity were determined. TPAD has comparable antibacterial activity to TPI on 14 bacterial strains, including four drug-resistant bacteria. Importantly, TPAD has significantly improved stability against enzymatic degradation and decreased hemolytic activity compared to TPI, indicating that it has better therapeutic potential. The induction of bacterial resistance using low concentrations of TPAD resulted in the activation of the QseC/B two-component system. Deletion of this system resulted in at least five-fold improvement of TPAD activity, and the combined use of TPAD with LED209, a QseC/B inhibitor, significantly enhanced the bactericidal effect against three classes of multidrug-resistant bacteria.

Influences of disulfide connectivity on structure and antimicrobial activity of tachyplesin I.

Abstract: Tachyplesin I is a potent antimicrobial peptide with broad spectrum of antimicrobial activity. It has 2 disulfide bonds and can form 3 disulfide bond isomers. In this study, the structure and antimicrobial activity of 3 tachyplesin I isomers (tachyplesin I, 3C12C, 3C7C) were investigated using molecular dynamic simulations, circular dichroism structural study, as well as antimicrobial activity and hemolysis assay. Our results suggest that in comparison to the native peptide, the 2 isomers (3C12C, 3C7C) have substantial structural and activity variations. The native peptide is in the ribbon conformation, while 3C12C and 3C7C possess remarkably different secondary structures, which are referred as "globular" and "beads" isomers, respectively. The substantially decreased hemolysis effects for these 2 isomers is accompanied by significantly decreased anti-gram-positive bacterial activity.

Role of the disulfide bond on the structure and activity of μ-conotoxin PIIIA in the inhibition of NaV1.4

Abstract: μ-Conotoxin PIIIA, a peptide toxin isolated from Conus purpurascens, blocks the skeletal muscle voltage-gated sodium channel NaV1.4 with significant potency. PIIIA has three disulfide bonds, which contribute largely to its highly constrained and stable structure. In this study, a combination of experimental studies and computational modeling were performed to assess the effects of deletion of the disulfide bonds on the structure and activity of PIIIA. The final results indicate that the three disulfide bonds of PIIIA are required to produce the effective inhibition of NaV1.4, and the removal of any one of the disulfide bonds significantly reduces its binding affinity owing to secondary structure variation, among which the Cys11–Cys22 is the most important for sustaining the structure and activity of PIIIA.

Antimicrobial peptide synthesis method with all amino acids being D-type amino acids

Abstract: The invention discloses an antimicrobial peptide synthesis method with all amino acids being D-type amino acids. The method comprises the following steps: activating resin with dichloromethane and N,N-dimethylformamide, and obtaining a straight-chain peptide KWCFRVCYRGICYRRCR* by a solid-phase synthesis method; cutting the resin with a mixed solution of trifluoroacetic acid, water, phenol and triisopropylsilane, performing rotary evaporation to remove the trifluoroacetic acid, adding frozen diethyl ether to precipitate a white solid, and performing freeze drying with a freezer drier to obtainsolid powder; constructing two pairs of disulfide bonds, wherein mercapto protective groups selected by 3-site,16-site cysteine are triphenylmethyl, mercapto protective groups selected by 7-site, 12-site cysteine are acetamide methyl. The method has the beneficial effect that the hemolytic activity is significantly reduced on the basis of maintaining the original antimicrobial activity.

The intriguing chemistry and biology of sulfur-containing natural products from marine microorganisms (1987–2020)

Abstract: Natural products derived from marine microorganisms have received great attention as a potential resource of new compound entities for drug discovery. The unique marine environment brings us a large group of sulfur-containing natural products with abundant biological functionality including antitumor, antibiotic, anti-inflammatory and antiviral activities. We reviewed all the 484 sulfur-containing natural products (non-sulfated) isolated from marine microorganisms, of which 59.9% are thioethers, 29.8% are thiazole/thiazoline-containing compounds and 10.3% are sulfoxides, sulfones, thioesters and many others. A selection of 133 compounds was further discussed on their structure–activity relationships, mechanisms of action, biosynthesis, and druggability. This is the first systematic review on sulfur-containing natural products from marine microorganisms conducted from January 1987, when the first one was reported, to December 2020.

Cationic Amphiphilic Peptides: Synthetic Antimicrobial Agents Inspired by Nature

Abstract: Antimicrobial peptides are ubiquitous in multicellular organisms and have served as defense mechanisms for their successful evolution and throughout their life cycle. These peptides are short cationic amphiphilic polypeptides of fewer than 50 amino acids containing either a few disulfide-linked cysteine residues with a characteristic β-sheet-rich structure or linear α-helical conformations with hydrophilic side chains at one side of the helix and hydrophobic side chains on the other side. Antimicrobial peptides cause bacterial cell lysis either by direct cell-surface damage via electrostatic interactions between the cationic side chains of the peptide and the negatively charged cell surface, or by indirect modulation of the host defense systems. Electrostatic interactions lead to bacterial cell membrane disruption followed by leakage of cellular components and finally bacterial cell death. Because of their unusual mechanism of cell damage, antimicrobial peptides are effective against drug-resistant bacteria and may therefore prove more effective than classical antibiotics in certain cases. Currently, around 3000 natural antimicrobial peptides from six kingdoms (bacteria, archaea, protists, fungi, plants, and animals) have been isolated and sequenced. However, only a few of them are under clinical trials and/or in the commercial development stage for the treatment of bacterial infections caused by antibiotic-resistant bacteria. Moreover, high structural complexity, poor pharmacokinetic properties, and low antibacterial activity of natural antimicrobial peptides hinder their progress in drug development. To overcome these hurdles, researchers have become increasingly interested in modification and nature-inspired synthetic antimicrobial peptides. This review discusses some of the recent studies reported on antimicrobial peptides.