Synthetic 1,2,3-triazole-linked glycoconjugates bind with high affinity to human galectin-3.

This work describes the synthesis of the 1,2,3-triazole amino acid-derived-3-O-galactosides 1-6 and the 1,2,3-triazole di-lactose-derived glycoconjugate 7 as potential galectin-3 inhibitors. The target compounds were synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition reaction ('click chemistry') between the azido-derived amino acids N3-ThrOBn, N3-PheOBn, N3-N-Boc-TrpOBn, N3-N-Boc-LysOBn, N3-O-tBu-AspOBn and N3-l-TyrOH, and the corresponding alkyne-based sugar 3-O-propynyl-GalOMe, as well as by click chemistry reaction between the azido-lactose and 2-propynyl lactose. Surface plasmon resonance (SPR) assays showed that all synthetic glycoconjugates 1-7 bound to galectin-3 with high affinity, but the highest binders were the amino acids-derived glycoconjugates 2 (KD 7.96µM) and 4 (KD 4.56µM), and the divalent lactoside 7 (KD1 0.15µM/KD2 19µM). Molecular modeling results were in agreement with SPR assays, since more stable interactions with galectin-3 were identified for glycoconjugates 2, 4 and 7. Regarding compounds 2 and 4, they established specific cation-π (Arg144) and ionic (Asp148) interactions, whereas glycoconjugate 7 was capable to bridge two independent galectin-3 CRDs, creating a non-covalent cross-link between two monomers and, thus, reaching a submicromolar affinity towards galectin-3.

Sensing soluble uric acid by Naip1-Nlrp3 platform.

Uric acid (UA), a product of purine nucleotide degradation able to initiate an immune response, represents a breakpoint in the evolutionary history of humans, when uricase, the enzyme required for UA cleavage, was lost. Despite being inert in human cells, UA in its soluble form (sUA) can increase the level of interleukin-1ß (IL-1ß) in murine macrophages. We, therefore, hypothesized that the recognition of sUA is achieved by the Naip1-Nlrp3 inflammasome platform. Through structural modelling predictions and transcriptome and functional analyses, we found that murine Naip1 expression in human macrophages induces IL-1ß expression, fatty acid production and an inflammation-related response upon sUA stimulation, a process reversed by the pharmacological and genetic inhibition of Nlrp3. Moreover, molecular interaction experiments showed that Naip1 directly recognizes sUA. Accordingly, Naip may be the sUA receptor lost through the human evolutionary process, and a better understanding of its recognition may lead to novel anti-hyperuricaemia therapies.

Ultrasensitive biosensor for detection of organophosphorus pesticides based on a macrocycle complex/carbon nanotubes composite and 1-methyl-3-octylimidazolium tetrafluoroborate as binder compound.

This work describes the highly sensitive detection of organophosphorus pesticides employing the cobalt(II) 4,4,4,4-tetrasulfo-phthalocyanine (CoTSPc) macrocycle complex, carbon nanotubes (CNT), and 1-methyl-3-octylimidazolium tetrafluoroborate (OMIM[BF4]). The technique is based on enzyme acetylcholinesterase (AChE) inhibition. The composite was characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and amperometry. The AChE was immobilized on the composite electrode surface by cross-linking with glutaraldehyde and chitosan. The synergistic action of the CoTSPc/CNT/OMIM[BF4] composite showed excellent electrocatalytic activity, with a low applied potential for the amperometric detection of thiocholine (TCh) at 0.0 V vs. Ag/AgCl. The calculated catalytic rate constant, k(cat), was 3.67 × 10(3) mol(-1) L s(-1). Under the optimum conditions, the inhibition rates of these pesticides were proportional to their concentrations in the ranges of 1.0 pmol L(-1) to 1.0 nmol L(-1) (fenitrothion), 2.0 pmol L(-1) to 8.0 nmol L(-1) (dichlorvos), and 16 pmol L(-1) to 5.0 nmol L(-1) (malathion).