Exploring the structure-activity relationship of Mincle ligands

<p>Mincle is a C-type lectin that plays a critical role in the body’s innate immune response to bacteria and fungi. Compounds identified as ligands for Mincle include trehalose and glycerol esters of complex long chain fatty acids. Harnessing its ability to activate the immune system, trehalose dimycolate has been used as a vaccine adjuvant and for anti-cancer treatment, highlighting the potential use of Mincle immunomodulators in a medical context. To further understand the receptor-ligand interactions and optimise biological activity, the structure-activity relationship of Mincle ligands was investigated through the synthesis and biological evaluation of a series of modified ligands. The preparation of carbohydrate modified trehalose dibehenates was attempted in order to assess the importance of hydroxylprotein interactions, and despite the syntheses being incomplete, improvements on literature methodologies for the regioselective modification of α,α′-D-trehalose were developed. Simplified analogues of the glycerol based natural products identified as Mincle ligands containing straight chain and iso-branched lipids were prepared to evaluate the significance of the branch and establish whether there is a relationship between lipid length and Mincle activation. The corresponding trehalose diester analogues were also synthesised to gauge the capacity of the protein to tolerate changes in the carbohydrate portion of ligands.</p>

Exploring the structure-activity relationship of Mincle ligands

<p>Mincle is a C-type lectin that plays a critical role in the body’s innate immune response to bacteria and fungi. Compounds identified as ligands for Mincle include trehalose and glycerol esters of complex long chain fatty acids. Harnessing its ability to activate the immune system, trehalose dimycolate has been used as a vaccine adjuvant and for anti-cancer treatment, highlighting the potential use of Mincle immunomodulators in a medical context. To further understand the receptor-ligand interactions and optimise biological activity, the structure-activity relationship of Mincle ligands was investigated through the synthesis and biological evaluation of a series of modified ligands. The preparation of carbohydrate modified trehalose dibehenates was attempted in order to assess the importance of hydroxylprotein interactions, and despite the syntheses being incomplete, improvements on literature methodologies for the regioselective modification of α,α′-D-trehalose were developed. Simplified analogues of the glycerol based natural products identified as Mincle ligands containing straight chain and iso-branched lipids were prepared to evaluate the significance of the branch and establish whether there is a relationship between lipid length and Mincle activation. The corresponding trehalose diester analogues were also synthesised to gauge the capacity of the protein to tolerate changes in the carbohydrate portion of ligands.</p>

Programmable site-selective labeling of oligonucleotides based on carbene catalysis

Site-selective modification of oligonucleotides serves as an indispensable tool in many fields of research including research of fundamental biological processes, biotechnology, and nanotechnology. Here we report chemo- and regioselective modification of oligonucleotides based on rhodium(I)-carbene catalysis in a programmable fashion. Extensive screening identifies a rhodium(I)-catalyst that displays robust chemoselectivity toward base-unpaired guanosines in single and double-strand oligonucleotides with structurally complex secondary structures. Moreover, high regioselectivity among multiple guanosines in a substrate is achieved by introducing guanosine-bulge loops in a duplex. This approach allows the introduction of multiple unique functional handles in an iterative fashion, the utility of which is exemplified in DNA-protein cross-linking in cell lysates.

Aptamer protective groups tolerate different reagents and reactions for regioselective modification of neomycin B

The aptameric protective group strategy is compatible with diverse reagents and reaction conditions for the synthesis of new neomycin B derivatives.

Immobilization of a Novel ESTBAS Esterase from Bacillus altitudinis onto an Epoxy Resin: Characterization and Regioselective Synthesis of Chloramphenicol Palmitate

Novel gene estBAS from Bacillus altitudinis, encoding a 216-amino acid esterase (EstBAS) with a signal peptide (SP), was expressed in Escherichia coli. EstBASΔSP showed the highest activity toward p-nitrophenyl hexanoate at 50 °C and pH 8.0 and had a half-life (T1/2) of 6 h at 50 °C. EstBASΔSP was immobilized onto a novel epoxy resin (Lx-105s) with a high loading of 96 mg/g. Fourier transform infrared (FTIR) spectroscopy showed that EstBASΔSP was successfully immobilized onto Lx-105s. In addition, immobilization improved its enzymatic performance by widening the tolerable ranges of pH and temperature. The optimum temperature of immobilized EstBASΔSP (Lx-EstBASΔSP) was higher, 60 °C, and overall thermostability improved. T1/2 of Lx-EstBASΔSP and free EstBASΔSP at 60 °C was 105 and 28 min, respectively. Lx-EstBASΔSP was used as a biocatalyst to synthesize chloramphenicol palmitate by regioselective modification at the primary hydroxyl group. Conversion efficiency reached 94.7% at 0.15 M substrate concentration after 24 h. Lx-EstBASΔSP was stable and could be reused for seven cycles, after which it retained over 80% of the original activity.

Regioselective DNA Modification and Directed Self-Assembly of Triangular Gold Nanoplates

As a class of emerging nanoparticles, gold nanotriangles (AuNTs) are characterized by unique structural anisotropy and plasmonic properties. The organization of AuNTs into well-defined architecture potentially promises collective properties that are difficult to produce by individual AuNTs. To date, however, the orientation-controlled self-assembly of AuNTs has been achieved with limited success. Here, we describe an effective and straightforward approach to induce directed self-assembly of AuNTs. By taking advantage of the uneven chemical reactivity of AuNT surfaces, we implement regioselective modification of the edges and the top/bottom surfaces with two different double-stranded DNA (dsDNA) sequences. By means of terminal single base pairing/unpairing, controlled assembly of the dsDNA-modified AuNTs evolves in a face-to-face or edge-to-edge manner based on blunt-end stacking interaction on an intentional region of the AuNTs, along with entropic repulsion by unpaired terminal nucleobases on the other region. This approach could be useful for achieving directed self-assembly of other anisotropic nanoparticles.

Regioselective oxidation of unprotected 1,4 linked glucans

Palladium-catalyzed alcohol oxidation allows the chemo- and regioselective modification of unprotected 1,4 linked glucans, shown here for 3-keto heptamaltoside azide.

Regioselective modification of unprotected glycosides

The regioselective modification of unprotected glycosides represents shortcuts in carbohydrate chemistry and enables efficient routes to complex derivatives.