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Xiao Li

Bio: Xiao Li is an academic researcher from Chinese Ministry of Education. The author has contributed to research in topics: Chemistry & Nicotinic agonist. The author has an hindex of 2, co-authored 4 publications receiving 8 citations.

Papers
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Journal ArticleDOI
TL;DR: The structure and function of the α9α10 nAChR are highlighted and studies of α-conotoxins targeting it are reviewed, including their three-dimensional structures, structure optimization strategies, and binding modes at the α 9α10nA chR, as well as their therapeutic potential.

22 citations

Journal ArticleDOI
TL;DR: TPAD has significantly improved stability against enzymatic degradation and decreased hemolytic activity compared to TPI, indicating that it has better therapeutic potential and at least five-fold improvement of TPAD activity.
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.

21 citations

Journal ArticleDOI
TL;DR: A formerly defined rat α7 nAChR targeting α-CTx Mr1.1 was chemically synthesized and displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.
Abstract: α-Conotoxins (α-CTxs) can selectively target nicotinic acetylcholine receptors (nAChRs) and are important drug leads for the treatment of cancer, chronic pain, and neuralgia. Here, we chemically synthesized a formerly defined rat α7 nAChR targeting α-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) α9α10 nAChR with a half-maximal inhibitory concentration (IC50) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the α10(+)α9(-) and α9(+)α9(-) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, α-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at hα9α10. Based on the Mr1.1-hα9α10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized hα9α10 with an IC50 of 4.0 nM. Furthermore, Mr1.1[S4Dap] displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.

7 citations

Journal ArticleDOI
TL;DR: In this article , the authors designed and synthesized three KIIIA analogues with one disulfide bond deleted, and their binding pattern to Nav1.7 was determined by molecular dynamics simulations.

3 citations

Journal ArticleDOI
TL;DR: In silico design of miniproteins with therapeutic potential through epitope grafting to the naturally occurring constrained peptide is an effective strategy.
Abstract: Naturally occurring constrained peptides are frequently used as scaffolds for bioactive peptide grating due to their high stability. Here, we used in silico methods to design several constrained peptides comprising a scorpion toxin scaffold, a MDM2 binding epitope, and a cluster of positively charged residues. The designed peptides displayed varied binding affinity to MDM2 despite differing by only one or two residues. One of the peptides, SC426, had nanomolar binding affinity (K-D=6.6 +/- 2.6 nm) to MDM2, and exhibited stronger inhibitory activity on the proliferation of HCT116 cells (p53-wild type) and SW480 cells (p53-mutant) than that of nutlin-3a. Binding mode analysis of the designed peptide at MDM2 suggests that the conserved "FWL" epitope was buried in the hydrophobic binding pocket, and the residues located at the periphery of the binding site contributed to the high binding affinity of SC426. Overall, in silico design of miniproteins with therapeutic potential through epitope grafting to the naturally occurring constrained peptide is an effective strategy.

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Journal ArticleDOI
TL;DR: In this paper , a review of the literature published in 2019 for marine natural products (MNPs) with 736 citations (724 for the period January to December 2021) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms.

98 citations

Journal ArticleDOI
TL;DR: A review of the literature published in 2020 for marine natural products (MNPs), with 757 citations (747 for the period January to December 2020) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms as discussed by the authors .

45 citations

Journal ArticleDOI
19 May 2021
TL;DR: 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 is presented in this article, where a selection of 133 compounds was further discussed on their structure-activity relationships, mechanisms of action, biosynthesis, and druggability.
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.

34 citations

Journal ArticleDOI
TL;DR: 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.
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.

29 citations

Journal ArticleDOI
TL;DR: In this article, the authors used methylene thioacetal as a disulfide surrogate in conotoxin-based peptide drugs for the treatment of neuropathic pain.
Abstract: α9-Containing nicotinic acetylcholine receptors (nAChRs) are key targets for the treatment of neuropathic pain. α-Conotoxin RgIA4 is a peptide antagonist of human α9α10 nAChRs with high selectivity. However, structural rearrangement reveals a potential liability for clinical applications. We herein report our designer RgIA analogues stabilized by methylene thioacetal as nonopioid analgesic agents. We demonstrate that replacing disulfide loop I [CysI-CysIII] with methylene thioacetal in the RgIA skeleton results in activity loss, whereas substitution of loop II [CysII-CysIV] can be accommodated. The lead molecule, RgIA-5524, exhibits highly selective inhibition of α9α10 nAChRs with an IC50 of 0.9 nM and much reduced degradation in human serum. In vivo studies showed that RgIA-5524 relieves chemotherapy-induced neuropathic pain in wild type but not α9 knockout mouse models, demonstrating that α9-containing nAChRs are necessary for the therapeutic effects. This work highlights the application of methylene thioacetal as a disulfide surrogate in conotoxin-based, disulfide-rich peptide drugs.

11 citations