Orthosteric and allosteric action of the C5a receptor antagonists

Published date : 11 Jun 2018

The C5a receptor (C5aR) is a G-protein-coupled receptor (GPCR) that can induce strong inflammatory response to the anaphylatoxin C5a. Targeting C5aR has emerged as a novel anti-inflammatory therapeutic method. However, developing potent C5aR antagonists as drugs has proven difficult. Here, we report two crystal structures of human C5aR in ternary complexes with the peptide antagonist PMX53 and a non-peptide antagonist, either avacopan or NDT9513727.

type
Journal Paper
journal
Natural Structural & Molecular Biology, Vol 25, June 2018, Pg 472-481, doi:10.1038/s41594-018-0067-z
Impact Factor
12.595

Allosteric Effects between the Antibody Constant and Variable Regions: A Study of IgA Fc Mutations on Antigen Binding

Published date : 08 Jun 2018

Therapeutic antibodies have shifted the paradigm of disease treatments from small molecules to biologics, especially in cancer therapy. Despite the increasing number of antibody candidates, much remains unknown about the antibody and how its various regions interact. Recent findings showed that the antibody constant region can govern localization effects that are useful in reducing side effects due to systemic circulation by the commonly used IgG isotypes. Given their localized mucosal effects, IgA antibodies are increasingly promising therapeutic biologics.

type
Journal Paper
journal
Antibodies 2018, 7(2), 20, doi: 10.3390/antib7020020

Stapled peptides as a new technology to investigate protein-protein interactions in human platelets

Published date : 25 May 2018

Platelets are blood cells with numerous crucial pathophysiological roles in hemostasis, cardiovascular thrombotic events and cancer metastasis. Platelet activation requires the engagement of intracellular signalling pathways that involve protein–protein interactions (PPIs). A better understanding of these pathways is therefore crucial for the development of selective anti-platelet drugs. New strategies for studying PPIs in human platelets are required to overcome limitations associated with conventional platelet research methods.

type
Journal Paper
journal
Chemical Science 2018, 9, Pg 4638-4643, doi: 10.1039/c8sc00284c

Impact Factor
8.668

Isolation and Identification of an Anthracimycin Analogue from Nocardiopsis kunsanensis, a Halophile from a Saltern, by Genomic Mining Strategy

Published date : 21 May 2018

Modern medicine is unthinkable without antibiotics; yet, growing issues with microbial drug resistance require intensified search for new active compounds. Natural products generated by Actinobacteria have been a rich source of candidate antibiotics, for example anthracimycin that, so far, is only known to be produced by Streptomyces species. Based on sequence similarity with the respective biosynthetic cluster, we sifted through available microbial genome data with the goal to find alternative anthracimycin-producing organisms.

type
Journal Paper
journal
Journal of Genomics, Vol. 6, 2018, Pg 63-73, doi:10.7150/jgen.24368
Impact Factor
2.402

Antimicrobial activity profiles of Amphiphilic Xanthone derivatives are a function of their molecular Oligomerization

Published date : 18 May 2018

Currently, membrane-targeting small antimicrobial peptidomimetics (SAP) are important in antibiotic development because bacteria appear to develop resistance to these surface-active compounds less readily. However, the molecular membrane-targeting action of SAPs has received little attention. In this study, we investigated the effect of oligomerization of amphiphilic xanthone, a model SAP, on its antimicrobial properties against both Gram-positive and Gram-negative bacteria.

type
Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018, doi: 10.1016/j.bbamem.2018.05.006
Impact Factor
3.498

Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket

Published date : 16 May 2018

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and rapidly result in the emergence of resistance. Recently Jia et al.

type
Journal Paper
journal
Chemical Science, 2018, doi: 10.1039/C8SC01262H
Impact Factor
8.668

Discovering novel SNPs that are correlated with patient outcome in a Singaporean cancer patient cohort treated with gemcitabine-based chemotherapy

Published date : 11 May 2018

Background
Single Nucleotide Polymorphisms (SNPs) can influence patient outcome such as drug response and toxicity after drug intervention. The purpose of this study is to develop a systematic pathway approach to accurately and efficiently predict novel non-synonymous SNPs (nsSNPs) that could be causative to gemcitabine-based chemotherapy treatment outcome in Singaporean non-small cell lung cancer (NSCLC) patients.

type
Journal Paper
journal
BMC Cancer (2018), 18:555, doi: 10.1186/s12885-018-4471-x
Impact Factor
3.288

Elucidating the bactericidal mechanism of action of the linear antimicrobial tetrapeptide BRBR-NH2

Published date : 11 May 2018

Linear antimicrobial peptides, with their rapid bactericidal mode of action, are well-suited for development as topical antibacterial drugs. We recently designed a synthetic linear 4-residue peptide, BRBR-NH2, with potent bactericidal activity against Staphylococcus aureus (MIC 6.25 μM), the main causative pathogen of human skin infections with an unknown mechanism of action.

type
Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018, doi: 10.1016/j.bbamem.2018.05.004
Impact Factor
3.498

Building predictive in vitro pulmonary toxicity assays using high-throughput imaging and artificial intelligence

Published date : 28 Apr 2018

Human lungs are susceptible to the toxicity induced by soluble xenobiotics. However, the direct cellular effects of many pulmonotoxic chemicals are not always clear, and thus, a general in vitro assay for testing pulmonotoxicity applicable to a wide variety of chemicals is not currently available. Here, we report a study that uses high-throughput imaging and artificial intelligence to build an in vitro pulmonotoxicity assay by automatically comparing and selecting human lung-cell lines and their associated quantitative phenotypic features most predictive of in vivo pulmonotoxicity.

type
Journal Paper
journal
Archives of Toxicology, April 2018, doi: 10.1007/s00204-018-2213-0
Impact Factor
5.901

Comparison of Charge Derivation Methods Applied to Amino Acid Parametrization

Published date : 27 Apr 2018

When using non-natural amino acids in computational simulations of proteins, it is necessary to ensure appropriate parameterization of the new amino acids toward the creation of appropriate input files. In particular, the charges on the atoms may have to be derived de novo and ad hoc for the new species. As there are many variables in the charge derivation process, an investigation was devised to compare different approaches and determine their effect on simulations. This was done with the purpose to identify the methods which produced results compatible with the existing parameters.

type
Journal Paper
journal
ACS Omega 2018, 3, Pg 4664-4673, doi: 10.1021/acsomega.8b00438