Structure-Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Anti-Angiogenic and Melanoma Anti-Tumor Activities.

To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, which selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure-activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif.

Inhibition of AcrAB-TolC enhances antimicrobial activity of phytochemicals in .

Introduction: The eons-long co-evolvement of plants and bacteria led to a plethora of interactions between the two kingdoms, in which bacterial pathogenicity is counteracted by plant-derived antimicrobial defense molecules. In return, efflux pumps (EP) form part of the resistance mechanism employed by bacteria to permit their survival in this hostile chemical environment. In this work we study the effect of combinations of efflux pump inhibitors (EPIs) and plant-derived phytochemicals on bacterial activity using 1692 (Pb1692) as a model system.

A comparison between 2D and 3D descriptors in QSAR modeling based on bio-active conformations.

QSAR models are widely and successfully used in many research areas. The success of such models highly depends on molecular descriptors typically classified as 1D, 2D, 3D, or 4D. While 3D information is likely important, e.

The Spliced Leader RNA Silencing (SLS) Pathway in Trypanosoma brucei Is Induced by Perturbations of Endoplasmic Reticulum, Golgi Complex, or Mitochondrial Protein Factors: Functional Analysis of SLS-Inducing Kinase PK3.

In the parasite Trypanosoma brucei, the causative agent of human African sleeping sickness, all mRNAs are -spliced to generate a common 5' exon derived from the spliced leader (SL) RNA. Perturbations of protein translocation across the endoplasmic reticulum (ER) induce the spliced leader RNA silencing (SLS) pathway. SLS activation is mediated by a serine-threonine kinase, PK3, which translocates from the cytosolic face of the ER to the nucleus, where it phosphorylates the TATA-binding protein TRF4, leading to the shutoff of SL RNA transcription, followed by induction of programmed cell death.

Phloretin, an Apple Phytoalexin, Affects the Virulence and Fitness of by Interfering With Quorum-Sensing.

The effects of phloretin a phytoalexin from apple, was tested on (Pb1692), an emerging soft-rot pathogen of potato. Exposure of Pb1692 to 0.2 mM phloretin a concentration that does not affect growth, or to 0.

Interkingdom Signaling Interference: The Effect of Plant-Derived Small Molecules on Quorum Sensing in Plant-Pathogenic Bacteria.

In the battle between bacteria and plants, bacteria often use a population density-dependent regulatory system known as quorum sensing (QS) to coordinate virulence gene expression. In response, plants use innate and induced defense mechanisms that include low-molecular-weight compounds, some of which serve as antivirulence agents by interfering with the QS machinery. The best-characterized QS system is driven by the autoinducer -acyl-homoserine lactone (AHL), which is produced by AHL synthases (LuxI homologs) and perceived by response regulators (LuxR homologs).

Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator.

Cystic Fibrosis (CF) is caused by mutations to the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. CFTR is composed of two membrane spanning domains, two cytosolic nucleotide-binding domains (NBD1 and NBD2) and a largely unstructured R-domain. Multiple CF-causing mutations reside in the NBDs and some are known to compromise the stability of these domains.

Discovery and Design of Novel Small Molecule GSK-3 Inhibitors Targeting the Substrate Binding Site.

The serine/threonine kinase, GSK-3, is a promising drug discovery target for treating multiple pathological disorders. Most GSK-3 inhibitors that were developed function as ATP competitive inhibitors, with typical limitations in specificity, safety and drug-induced resistance. In contrast, substrate competitive inhibitors (SCIs), are considered highly selective, and more suitable for clinical practice.

Phenotypic and molecular characteristics of CF patients carrying the I1234V mutation.

Background: The Mutation I1234V is a CF causing mutation; however the mechanisms leading to loss of function are not fully understood. In this study, we aimed to characterize phenotypically individuals with the I1234V variant, and to gain a structural point of view of the mutant CFTR using computational studies.

Methods: We conducted a retrospective descriptive study, reviewing the clinical records of 9 Israeli patients.

Direct Binding of Salicylic Acid to -Acyl-Homoserine Lactone Synthase.

Salicylic acid (SA) is a hormone that mediates systemic acquired resistance in plants. We demonstrated that SA can interfere with group behavior and virulence of the soft-rot plant pathogen spp. through quorum sensing (QS) inhibition.

An Ancient CFTR Ortholog Informs Molecular Evolution in ABC Transporters.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel central to the development of secretory diarrhea and cystic fibrosis. The oldest CFTR ortholog identified is from dogfish shark, which retains similar structural and functional characteristics to the mammalian protein, thereby highlighting CFTR's critical role in regulating epithelial ion transport in vertebrates. However, the identification of an early CFTR ortholog with altered structure or function would provide critical insight into the evolution of epithelial anion transport.

Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl-β-phosphate scaffold.

Overexpression of ecto-nucleotide pyrophosphatase-1 (NPP1) is associated with diseases such as calcium pyrophosphate dihydrate deposition disease, calcific aortic valve disease, and type 2 diabetes. In this context, NPP1 inhibitors are potential drug candidates for the treatment of these diseases. The present study focuses on the analysis of the structure-activity relationship of NPP1 inhibitors based on acyclic uracil-nucleotides.

Novel inhibitors of leukocyte transendothelial migration.

Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells.

Guaiacol as a drug candidate for treating adult polyglucosan body disease.

Adult polyglucosan body disease (APBD) is a late-onset disease caused by intracellular accumulation of polyglucosan bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid-Schiff reagent, which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts.

Ligand binding to a remote site thermodynamically corrects the F508del mutation in the human cystic fibrosis transmembrane conductance regulator.

Many disease-causing mutations impair protein stability. Here, we explore a thermodynamic strategy to correct the disease-causing F508del mutation in the human cystic fibrosis transmembrane conductance regulator (hCFTR). F508del destabilizes nucleotide-binding domain 1 (hNBD1) in hCFTR relative to an aggregation-prone intermediate.

Structural stability of purified human CFTR is systematically improved by mutations in nucleotide binding domain 1.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is an ABC transporter containing two transmembrane domains forming a chloride ion channel, and two nucleotide binding domains (NBD1 and NBD2). CFTR has presented a formidable challenge to obtain monodisperse, biophysically stable protein. Here we report a comprehensive study comparing effects of single and multiple NBD1 mutations on stability of both the NBD1 domain alone and on purified full length human CFTR.

A novel image-based high-throughput screening assay discovers therapeutic candidates for adult polyglucosan body disease.

Glycogen storage disorders (GSDs) are caused by excessive accumulation of glycogen. Some GSDs [adult polyglucosan (PG) body disease (APBD), and Tarui and Lafora diseases] are caused by intracellular accumulation of insoluble inclusions, called PG bodies (PBs), which are chiefly composed of malconstructed glycogen. We developed an APBD patient skin fibroblast cell-based assay for PB identification, where the bodies are identified as amylase-resistant periodic acid-Schiff's-stained structures, and quantified.

Specific stabilization of CFTR by phosphatidylserine.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR, ABCC7) is a plasma membrane chloride ion channel in the ABC transporter superfamily. CFTR is a key target for cystic fibrosis drug development, and its structural elucidation would advance those efforts. However, the limited in vivo and in vitro stability of the protein, particularly its nucleotide binding domains, has made structural studies challenging.

Plant phenolic volatiles inhibit quorum sensing in pectobacteria and reduce their virulence by potential binding to ExpI and ExpR proteins.

Quorum sensing (QS) is a population density-dependent regulatory system in bacteria that couples gene expression to cell density through accumulation of diffusible signaling molecules. Pectobacteria are causal agents of soft rot disease in a range of economically important crops. They rely on QS to coordinate their main virulence factor, production of plant cell wall degrading enzymes (PCWDEs).

Potentiators exert distinct effects on human, murine, and Xenopus CFTR.

VX-770 (Ivacaftor) has been approved for clinical usage in cystic fibrosis patients with several CFTR mutations. Yet the binding site(s) on CFTR for this compound and other small molecule potentiators are unknown. We hypothesize that insight into this question could be gained by comparing the effect of potentiators on CFTR channels from different origins, e.

Design of Compact Biomimetic Cellulose Binding Peptides as Carriers for Cellulose Catalytic Degradation.

The conversion of biomass into biofuels can reduce the strategic vulnerability of petroleum-based systems and at the same time have a positive effect on global climate issues. Lignocellulose is the cheapest and most abundant source of biomass and consequently has been widely considered as a source for liquid fuel. However, despite ongoing efforts, cellulosic biofuels are still far from commercial realization, one of the major bottlenecks being the hydrolysis of cellulose into simpler sugars.

Asymmetric DNA-search dynamics by symmetric dimeric proteins.

We focus on dimeric DNA-binding proteins from two well-studied families: orthodox type II restriction endonucleases (REs) and transcription factors (TFs). Interactions of the protein's recognition sites with the DNA and, particularly, the contribution of each of the monomers to one-dimensional (1D) sliding along nonspecific DNA were studied using computational tools. Coarse-grained molecular dynamics simulations of DNA scanning by various TFs and REs provide insights into how the symmetry of a homodimer can be broken while they nonspecifically interact with DNA.

Sliding of p53 along DNA can be modulated by its oligomeric state and by cross-talks between its constituent domains.

The p53 protein is a homotetrameric transcription factor whose monomers comprise several domains. Although its organization with and without DNA was elucidated recently, characterizing the p53-DNA complex at the atomic level remains challenging because of its many disordered regions. Here we use computational models to predict the wiring of the four chains composing p53 and study its sliding dynamics along DNA in different oligomeric states.

The mechanism of papain inhibition by peptidyl aldehydes.

Various mechanisms for the reversible formation of a covalent tetrahedral complex (TC) between papain and peptidyl aldehyde inhibitors were simulated by DFT calculations, applying the quantum mechanical/self consistent reaction field (virtual solvent) [QM/SCRF(VS)] approach. Only one mechanism correlates with the experimental kinetic data. The His-Cys catalytic diad is in an N/SH protonation state in the noncovalent papain-aldehyde Michaelis complex.