Attachment Of Side Chains Research Articles

DOCKTITE—A Highly Versatile Step-by-Step Workflow for Covalent Docking and Virtual Screening in the Molecular Operating Environment

The formation of a covalent bond with the target is essential for a number of successful drugs, yet tools for covalent docking without significant restrictions regarding warhead or receptor classes are rare and limited in use. In this work we present DOCKTITE, a highly versatile workflow for covalent docking in the Molecular Operating Environment (MOE) combining automated warhead screening, nucleophilic side chain attachment, pharmacophore-based docking, and a novel consensus scoring approach. The comprehensive validation study includes pose predictions of 35 protein/ligand complexes which resulted in a mean RMSD of 1.74 Å and a prediction rate of 71.4% with an RMSD below 2 Å, a virtual screening with an area under the curve (AUC) for the receiver operating characteristics (ROC) of 0.81, and a significant correlation between predicted and experimental binding affinities (ρ = 0.806, R(2) = 0.649, p < 0.005).

Homogeneous ring opening graft polymerization of ɛ-caprolactone onto xylan in dual polar aprotic solvents.

Homogeneous ring-opening graft polymerization (ROGP) of ɛ-caprolactone (ɛ-CL) onto xylan was investigated in dual polar aprotic solvents, N,N-dimethylformamide/lithium chloride (DMF/LiCl), N,N-dimethylacetamide/LiCl (DMAc/LiCl), and 1-methyl-2-pyrrolidinone/LiCl (NMP/LiCl). The effects of reaction solvents, temperature, and the molar ratio of ɛ-CL to anhydroxylose units (AXU) on the degree of substitution (DS) of xylan-graft-poly(ɛ-caprolactone) (xylan-g-PCL) copolymers and the degree of polymerization (DP) of the attached PCL side chains were investigated. FT-IR and NMR analyses provided the evidence of the occurrence of ROGP reaction. The thermal stability of xylan increased upon ROGP reaction due to the increased length of PCL side chains. With the increased attachment of PCL side chains, the tensile strength and Young's modulus of the films decreased, whereas the elongation at break increased. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) observations provided the evidences of the increased film properties due to the attachment of PCL side chains.

Identification and characterization of a tyramine-glutamate ligase (MfnD) involved in methanofuran biosynthesis.

Methanofuran is the first in a series of coenzymes involved in the reduction of carbon dioxide to methane. All methanofuran structural variants contain a basic core structure of 4-[N-(γ-l-glutamyl-γ-l-glutamyl)-p-(β-aminoethyl)phenoxymethyl]-2-(aminomethyl)furan (APMF-(Glu)2) with different attached side chains depending on the source organism. Recently, we discovered the biosynthetic route for the production of 5-(aminomethyl)-3-furanmethanol-phosphate (F1-P), a precursor to the furan moiety of methanofuran. However, how the γ-linked glutamates are incorporated into methanofuran's structure remains unknown. Here, we report the identification of an ATP-grasp enzyme encoded by the gene Mefer_1180 in Methanocaldococcus fervens (the homologue of MJ0815 in Methanocaldococcus jannaschii, annotated as MfnD) that catalyzes the ATP-dependent addition of one glutamate to tyramine via a γ-linked amide bond. The occurrence of this reaction is consistent with the presence of γ-glutamyltyramine in cell extracts of M. jannaschii. Our steady-state kinetic analysis of the recombinant enzyme showed that MfnD exhibits a catalytic ability comparable to other ATP-grasp enzymes such as the Escherichia coli glutathione synthetase (GS), with a similar apparent kcat and KM. In addition, its activity is divalent metal-dependent, with the highest activity observed with Mn(2+). The previously solved crystal structure of MfnD from Archaeoglobus fulgidus exhibits a classical ATP-grasp fold with three structural domains; the ATP-binding and metal-binding motifs are conserved in MfnD as seen in other ATP-grasp enzymes. We used site-directed mutagenesis and kinetic analysis to demonstrate that Arg251 is an important residue for both catalysis and glutamate binding. By comparing the active site of MfnD with GS and by molecular docking substrates to the MfnD active site, we predicted the possible glutamate- and tyramine-binding pocket. This is the first report describing the enzymology of the incorporation of the initial l-glutamate molecule into the methanofuran structure. It also provides the first example of an ATP-grasp enzyme activating the γ-carboxylate of glutamate as substrate.

Chemically modified palm kernel oil ester: A possible sustainable alternative insulating fluid

The demand for a sustainable and non-toxic alternative insulating fluid has been on the increase because of the negative environmental impact of mineral-based insulating fluids. Natural ester appeared to be a viable alternative, but it has poor thermo-oxidative properties and higher melting temperature. This report presents the influence of chemical modification on the properties of natural ester-based alternative insulating fluid. Alkyl ester derivatives were synthesized from laboratory purified palm kernel oil. A straight chain alkyl ester was first synthesized to enhance the flow properties of the oil. It was then followed by a process that converts the double bond to an epoxy group. Side-branched ester samples were synthesized from the laboratory synthesized epoxy alkyl ester of palm kernel oil. The chemical modification was performed through esterification reaction involving the epoxy alkyl ester of palm kernel oil and acid anhydrides under nitrogen and in the presence of boron trifluoride etherate as catalyst. The reactions were monitored and the products confirmed using FTIR and GC–MS. The melting point and thermo-oxidative stability of the fluids were examined using Differential Scanning Calorimetry (DSC). The melting point of the ester derivatives was found to reduce with side chain attachment and antioxidant significantly improved the thermal stability. The dielectric behavior and electrical breakdown properties of the ester derivatives were analyzed and compared. The dielectric loss was dominated by mobile charged particles and the charged particles appeared to exhibit faster dynamics compared with purified palm kernel oil. This may be attributed to the mobility of the charges which is related to the viscosity of the esters. The esters possessed excellent breakdown strengths suggest that the processing to optimize the physical properties did not have a negative influence on the electrical breakdown strength. This product may prove useful as an insulation fluid in Electrical Power Transformers.

A comparison of genes involved in sphingan biosynthesis brought up to date.

Microbial polysaccharides have a wide range of functional properties and show high relevance in industrial applications. The possibility to create tailor-made polysaccharides by genetic engineering will further enhance the product portfolio and may open new fields of application. Here, we have examined in detail the recently sequenced genome of the welan-producing strain Sphingomonas sp. ATCC 31555 to identify the complete welan cluster and further genes involved in EPS production. The corresponding genes were compared on the nucleotide and amino acid sequence level to the EPS clusters of the described gellan-producing Sphingomonas elodea ATCC 31461, diutan-producing Sphingomonas sp. ATCC 53159, and the S-88-producing Sphingomonas sp. ATCC 31554 strains. We also compared the previously mentioned strains to each other and included the genes upstream of the main cluster in gellan and welan cluster. The cluster organization of Sphingomonas strain S-7 was also compared based on previous hybridization experiments, without nucleotide sequences. We have found that the occurrence of genes in all biosynthesis clusters is connected to the structures of the various produced sphingans. Along these lines, homologous genes responsible for the assembly of the identical repeating unit generally show high sequence identity, whereas genes for putative side chain attachment urf31, urf31.4, and urf34 vary more in distinct areas. Moreover, gene clusters for biosynthesis of diutan, welan, gellan, and S-88 as well as S-7 are similar in general organization but differ in location and arrangement of some genes. Finally, we summarized genetic and mutational engineering approaches toward modified sphingan variants as described in literature.

Dual-Component System Dimethyl Sulfoxide/LiCl as a Solvent and Catalyst for Homogeneous Ring-Opening Grafted Polymerization of ε-Caprolactone onto Xylan

The preparation of xylan-graft-poly(ε-caprolactone) (xylan-g-PCL) copolymers was investigated by homogeneous ring-opening polymerization (ROP) in a dual-component system containing Lewis base LiCl and strong polar aprotic solvent dimethyl sulfoxide (DMSO). DMSO/LiCl acted as solvent, base, and catalyst for the ROP reaction. The effects of the parameters, including the reaction temperature, molar ratio of ε-caprolactone (ε-CL) to anhydroxylose units (AXU) in xylan, and reaction time, on the degree of substitution (DS) and weight percent of PCL side chain (WPCL) were investigated. The results showed that xylan-g-PCL copolymers with low DS in the range of 0.03-0.39 were obtained under the given conditions. The Fourier transform infrared spectroscopy (FTIR), (1)H nuclear magnetic resonance (NMR), (13)C NMR, (1)H-(1)H correlation spectroscopy (COSY), and (1)H-(13)C correlation two-dimensional (2D) NMR [heteronuclear single-quantum coherence (HSQC)] characterization provided more evidence of the attachment of side chains onto xylan. Only one ε-CL was confirmed to be attached onto xylan with each side chain. Integration of resonances assigned to the substituted C2 and C3 in the HSQC spectrum also indicated 69.23 and 30.77% of PCL side chains attached to AXU at C3 and C2 positions, respectively. Although the attachment of PCL onto xylan led to the decreased thermal stability of xylan, the loss of unrecovered xylan fractions with low molecular weight because of the high solubility of xylan in DMSO/LiCl resulted in the increased thermal stability of the samples. This kind of xylan derivative has potential application in environmentally friendly and biodegradable materials considering the good biodegradability of xylan and PCL.

Modification of pectin and hemicellulose polysaccharides in relation to aril breakdown of harvested longan fruit.

To investigate the modification of cell wall polysaccharides in relation to aril breakdown in harvested longan fruit, three pectin fractions (WSP, water soluble pectin; CSP, CDTA-soluble pectin; ASP, alkali soluble pectin) and one hemicellulose fraction (4 M KOH-SHC, 4 M KOH-soluble hemicellulose) were extracted, and their contents, monosaccharide compositions and molecular weights were evaluated. As aril breakdown intensified, CSP content increased while ASP and 4 M KOH-SHC contents decreased, suggesting the solubilization and conversion of cell wall components. Furthermore, the molar percentage of arabinose (Ara), as the main component of the side-chains, decreased largely in CSP and ASP while that of rhamnose (Rha), as branch point for the attachment of neutral sugar side chains, increased during aril breakdown. Analysis of (Ara + Gal)/Rha ratio showed that the depolymerization of CSP and ASP happened predominantly in side-chains formed of Ara residues. For 4 M KOH-SHC, more backbones were depolymerized during aril breakdown. Moreover, it was found that the molecular weights of CSP, ASP and 4 M KOH-SHC polysaccharides tended to decrease as aril breakdown intensified. These results suggest that both enhanced depolymerization and structural modifications of polysaccharides in the CSP, ASP and 4 M KOH-SHC fractions might be responsible for aril breakdown of harvested longan fruit.

Antifouling activity of synthetic γ-hydroxybutenolides

The desire to provide greener antifouling (AF) biocides for incorporation into marine paints has led to the discovery of many AF natural products. However, economical and sustainable supply of these natural products is often lacking. Twenty one structurally diverse γ-hydroxybutenolides – inspired by two natural AF sesterterpene γ-hydroxybutenolides (cavernosolide and lintenolide A) – were synthesized and tested for in vitro AF efficacy against the marine bryozoan larvae (Bugula neritina) and algae (Isochrysis galbana). The most potent analogues (EC50 ca. 2 μg/mL) had AF activity comparable to the natural products (EC50 ca. 0.6 μg/mL). Sites of attachment of side chains to the γ-hydroxybutenolide core structure had little effect on AF activity, however a clear relationship was established between lipophilicity and AF activity. Four analogues were chosen for field trials, incorporated into paints and deployed on panels in the marine environment. These analogues were chosen to reflect logistics of large scale synthesis and to provide representation of diverse structural motifs. Without any primary or co-biocides (except ZnO as a paint pigment), two analogues demonstrated a pronounced AF effect by resisting biofouling for over 18 weeks, compared to the ZnO control of between 7 and 10 weeks. Fine tuning of the structural motifs and/or the inclusion of co-biocides in paint formulations provide the potential to increase AF efficacy further.

A Convenient Route For The Alkoxylation Of Biodiesel And Its Influence On Cold Flow Properties

The attachment of alkoxy side chains to biodiesel and the associated effects on its cold flow properties are reported. High oleic methyl ester biodiesel was epoxidized using peroxy formic acid and subsequently alkoxylated using nine different alcohols employing BF3-ethereate complex as catalyst. A low molar excess for alcohols was used at moderately low reaction temperatures (40–50°C). A high conversion for attachment of alkoxy group ranging 84%–93% was achieved with excellent selectivity. Cloud points, pour points, and kinematic viscosities were measured to evaluate the cold flow properties of modified biodiesel. The lowest cloud point –11°C and pour point –14°C were obtained with n-decoxy biodiesel. Elevated kinematic viscosities were observed for all alkoxylated products. The lowest kinematic viscosity (6.26 mm2·s−1) was observed for methoxy biodiesel. Gas chromatography mass spectrometry (GC-MS), proton nuclear magnetic resonance (1H NMR), 13C NMR, and Fourier transform infrared (FT-IR) were used for structural elucidation. The reported alkoxylation route has high conversion rate and is convenient to implement.

FRI0044 IL-1 dependent SYNDECAN-4 signal transduction is mediated by its heparan sulfate side chains in RA synovial fibroblasts

BackgroundIn rheumatoid arthritis (RA) pathogenesis, activated synovial fibroblasts (SFs) play an important role, because of their tumor-like and agressive behavior. This phenotype is promoted by a steady stimulation with growth-factors...

Locations of the Hydrophobic Side Chains of Lipoglycopeptides Bound to the Peptidoglycan of Staphylococcus aureus

Glycopeptides whose aminosugars have been modified by attachment of hydrophobic side chains are frequently active against vancomycin-resistant microorganisms. We have compared the conformations of six such fluorinated glycopeptides (with side chains of varying length) complexed to cell walls labeled with d-[1-(13)C]alanine, [1-(13)C]glycine, and l-[ε-(15)N]lysine in whole cells of Staphylococcus aureus. The internuclear distances from (19)F of the bound drug to the (13)C and (15)N labels of the peptidoglycan, and to the natural abundance (31)P of lipid membranes and teichoic acids, were determined by rotational-echo double resonance NMR. The drugs did not dimerize, and their side chains did not form membrane anchors but instead became essential parts of secondary binding to pentaglycyl bridge segments of the cell-wall peptidoglycan.

Molecular, conformational, and optical characteristics of poly(dodecylammonium-2-acrylamido-2-methylpropanesulfonate) in organic solvents

A number of samples of poly(dodecylammonium-2-acrylamido-2-methylpropanesulfonate)—a comb-like polymer with ionically bound side chains—are obtained by the polymerization of dodecylammonium-2-acrylamido-2-methylpropanesulfonate in an aqueous medium. The samples are obtained in a wide molecular-mass range. Molecular, hydrodynamic, and optical characteristics of the samples are determined by the methods of sedimentation-diffusion analysis, viscometry, and flow birefringence in dilute polymer solutions in chloroform and dimethyl sulfoxide containing small amounts of 0.1 M LiCl. It is shown that conformational and optical characteristics based on hydrodynamic and dynamo-optic investigations agree with the data available for acrylic and methacrylic polymers with the same lengths of side groups. In other words, the character of attachment (covalent or ionic) of long side chains to the backbone has no effect on the conformational and optical characteristics of macromolecules.

Pore morphologies and diffusion within hydrated polyelectrolyte membranes: Homogeneous vs heterogeneous and random side chain attachment

Using dissipative particle dynamics pore morphologies within model ionomer membranes are simulated. The ionomers are composed of hydrophobic backbones and side chains that are end-linked with a hydrophilic acid containing site. The separation distance between successive branching points is bi-modal, being alternating short (distance x) and long (distance y). The dependence of morphology on ion exchange capacity and separation distance is investigated. Phase separated morphologies were calculated at a water content of 16 vol. %. An increase of side chain density results in a decreasing size of the water containing pores, distance between them and decreasing Bragg spacing. For fixed side chain density, an increase in difference between the longer and shorter separation distance (y - x) results in a larger Bragg spacing. Monte Carlo calculations demonstrate that a large majority of the water is contained within a percolating network that allows for long-range diffusion. Diffusion constants vary drastically with architecture: Diffusion is fastest for architectures for which the side chains are highly non-uniformly distributed (y ≫ x). For architectures with the same side chain density, the tracer diffusion constants increase linearly with increase of the asymmetry ratio y∕x (y > x). This is caused by the cooperative action of those terminal acidic sites that are topologically close together, allowing them to arrange pair wise along the pore walls and make the pores larger. We verified that for polymer architectures that mimick Nafion1200 similar trends are obtained, resulting in increased H(2)O, O(2), and H(2) permeation for statistical side chain distribution as compared to a uniform distribution of side chains. This trend is most pronounced for H(2)O and less pronounced for H(2).

Regioregularity and Intrachain Ordering: Impact on the Nanostructure and Charge Transport in Two-Dimensional Assemblies of Poly(3-hexylthiophene)

The properties of supramolecular assemblies in conjugated macromolecular systems are strongly dependent on single chain effects. We report that differences in regioregularity (RR) of side chain attachment in poly(3-hexylthiophene) (P3HT) as small as ca. 4% are sufficient to induce dramatic changes in the electronic and morphological properties of the material. Casting the electronic absorption spectra in the framework of Spano’s model reveals that the conjugation length is surprisingly sensitive to RR, with differences in free exciton bandwidth between the two P3HT samples approaching 73 meV. The enhanced main chain planarization motivates a concomitant increase in nanofibril width as well as crystallinity observed in thin films of the higher RR variant. This observation correlates well with the field effect mobilities that are attenuated by 1 to 2 orders of magnitude in the lower RR polymer film. We suggest that the increased intrachain order coupled with a reduced fraction of grain boundaries in the higher RR film is responsible for the reported differences.

Structure of arabinogalactan-protein from Acacia gum: From porous ellipsoids to supramolecular architectures

The structure of the arabinogalactan-protein (AGP) fraction of the gum exudate of Acacia senegal (gum Arabic) isolated from hydrophobic interaction chromatography was investigated using HPSEC-MALLS, small angle neutron scattering and TEM observations. Literature reported that the AGP structure of gum Arabic adopts a very compact conformation in solution due to the attachment of short arabinoside side chains and much larger blocks of carbohydrate to the polypeptidic backbone. The present study revealed that AGP in solution had a weight average molecular weight Mw of 1.86×106gmol−1 and a radius of gyration Rg of 30nm. In addition, two exponent values were identified in the Rg, [η], Rh and ρ vs. Mw relationships highlighting two types of conformations depending on the molecular weight range considered: a low molar mass population with long-chain branching and a compact conformation and a high molar mass population with short-chain branching and an elongated conformation. AGP would behave in solution as a branched or hyper-branched polymer with conformations ranging from globular to elongated shape depending on the size of the carbohydrate branches. Small angle scattering form factor revealed an elongated average conformation corresponding to a triaxial ellipsoid while inverse Fourier transform of the scattering form factor gave a maximum dimension for AGP of 64nm. Transmission electron microscopy highlighted the existence of two types of flat objects with thicknesses below 3–5nm, single particles with a more or less anisotropic spheroidal shape and aggregated structures with a more elongated shape. A remarkable feature of all particle morphologies was the presence of an outer structure combined to an inner more or less porous network of interspersed chains or interacting structural blocks, as previously found for the arabinogalactan (AG) main molecular fraction of Acacia gum. However, clear differences were observed in the density and morphology of the inner porous network, probably highlighting differences in the degree of branching. The existence of assembled AG as part of the AGP family was confirmed using TEM micrographs at high resolution. Fused AGP dimers, trimers, tetramers and multimers were also identified. These molecular assemblies questioned about the nature of interactions involved.

Yeast mannan structure necessary for co-aggregation with Lactobacillus plantarum ML11-11

Lactic acid bacteria (LAB) Lactobacillus plantarum ML11-11, an isolate from Fukuyama pot vinegar, and yeast Saccharomyces cerevisiae form significant mixed-species biofilm with direct cell–cell contact. Co-aggregation of L. plantarum ML11-11 and S. cerevisiae cells, mediated by the interaction between surface protein(s) on L. plantarum ML11-11 cells and surface mannan of S. cerevisiae cells, contributes significantly to mixed-species biofilm formation. In this study, co-aggregation activities of yeast mutants that were deleted of genes related to mannan biosynthesis were investigated to clarify the mannan structures essential for interaction with L. plantarum ML11-11. Among the 12 deletion mutants which had various incomplete mannan structures, only the mnn2 mutant lost the co-aggregation activity. In the mnn2 mutant, the gene coding the activity of attaching first branching mannose residue to mannan main chain is deleted and therefore the mnn2 mutant has unbranched mannan. From this result, it is clarified that the specific structure, consisted of mannan main chain to which are attached side chains containing one or more mannose residues, is critical for co-aggregation with L. plantarum ML11-11.

MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM: Extracellular matrix regulation of skeletal muscle formation1,2

Skeletal muscle development and growth is a complex process that involves the interaction of muscle cells with their extracellular environment. Because muscle development involves the interaction of the cell surface and extracellular matrix molecules, research focus has been placed on the proteoglycans. Proteoglycans are macromolecules containing a central core protein with attached carbohydrates, called glycosaminoglycans, that are located at both the cell surface and the extracellular matrix. Research focus has been placed on understanding the mechanisms of the membrane-associated heparan sulfate proteoglycans, syndecan-4 and glypican-1, which are both capable of regulating cellular responsiveness to fibroblast growth factor 2 (FGF2). Fibroblast growth factor 2 is a potent stimulator of muscle cell proliferation and a strong inhibitor of differentiation. Studies on syndecan-4 and glypican-1 show that these proteoglycans differentially regulate muscle cell proliferation, differentiation, and cellular responsiveness to FGF2 with syndecan-4 predominantly modulating muscle cell proliferation and glypican-1 modulating differentiation. Site-directed mutagenesis approaches were used to define the effect of the syndecan-4 and glypican-1 covalently attached side chains on their activity. In general, a functional association was found between the glycosaminoglycan and N-glycosylated chains attached to the central core proteins of syndecan-4 and glypican-1 affecting their regulation of muscle cell proliferation, differentiation, and FGF2 responsiveness. Current research efforts are directed at identifying the cellular signaling pathways modulated by syndecan-4 and glypican-1.

Some Mechanical and Thermal Properties of PC/ABS Blends

A series of blends of Acrylonitrile-Butadiene-Styrene (ABS) and Polycarbonate (PC) were prepared and some of their thermal and mechanical properties were determined. The Young’s modulus changed gradually and monotonically with the polycarbonate content. This effect was tentatively explained as the antiplasticization of the PC which is ascribed to the chain mobility, which permits the PC chains to pack more tightly, to the secondary cross-linking between the PC chains, or to the secondary attachment of bulky side-chains to the PC, thus producing steric hindrance to the rotation of the PC main chains. The experimental values found for the impact strength were intermediate between those of the neat polymers, depending upon the dispersed rubber particles of butadiene in the matrix of SAN (Styrene-Acrylonitrile), and the dispersed PC particles which generally make the ABS more brittle. A maximum value of about 88 KJ/m2 for the impact strength was observed for the blend with 90% PC. This may be attributed to the strong polymer-polymer interactions for this particular composition. The variations in the heat deflection temperature HDT and the Vicat softening point with the blend composition were very similar, and allowed us to assume that the phase inversion between the matrices of the two polymers takes place at 50% PC. The morphology of the blends revealed by SEM observation, show a co-continuous structure.

Bioinspired Total Synthesis and Human Proteasome Inhibitory Activity of (−)-Salinosporamide A, (−)-Homosalinosporamide A, and Derivatives Obtained via Organonucleophile Promoted Bis-cyclizations

A full account of concise, enantioselective syntheses of the anticancer agent (-)-salinosporamide A and derivatives, including (-)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A(1,3)-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (-)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.

On resin amino acid side chain attachment strategy for the head to tail synthesis of new glutamine containing gramicidin-S analogs and their antimicrobial activity

The alarming increase in infections caused by multiple drug resistant bacteria including methicillin-resistant Staphylococcus aureus has prompted a desperate search for new antimicrobials. Augmenting the discoveries of completely new scaffolds with antimicrobial activity are efforts aimed at modifying existing molecules to optimize activity or reduce toxicity. We report herein the parallel solid-phase synthesis of analogues of the cationic antimicrobial peptide gramicidin S (GS) using amino acid side chain attachment strategy. The ornithine (Orn) residues were replaced by glutamine (Gln) and the aromatic d-phenylalanine (Phe) were replaced by different aromatic d-amino acids. Additional Gln containing GS analogues with all the possible combinations of the hydrophobic amino acids valine and leucine were also synthesized. In this work we also report the antibacterial activity of these analogs against several clinically-important drug-resistant Gram-positive and Gram-negative pathogens.