The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative stress. Inhibition of the interaction between NRF2 and its main negative regulator KEAP1 is an attractive strategy toward neuroprotective agents. We report here the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the KEAP1/NRF2 protein–protein interaction. Peptide SAR at one residue is utilized as a tool to probe structural changes within a specific pocket of the KEAP1 binding site. We used structural information from peptide screening at the P2 pocket, noncovalent small-molecules inhibitors, and the outcome from an explorative SAR at position 5 of THIQs to identify a series of neutral THIQ analogs that bind to KEAP1 in the low micromolar range. These analogs establish new H-bond interactions at the P3 and P2 pockets allowing the replacement of the carboxylic acid functionality by a neutral primary carboxamide. X-ray crystallographic studies reveal the novel binding mode of these molecules to KEAP1.

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A novel approach for multivalent targeting by using gold nanoparticles noncovalently decorated by tight functionalization with a cone-glycocalixarene bearing four mannose units is reported. The targeting efficiency of these multivalent nanoparticles is shown to be remarkably improved compared to that of nanoparticles bearing a monovalent mannosylated derivative.

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SummaryFour novel calix[4]arene-based glycoclusters were synthesized by conjugating the saccharide units to the macrocyclic scaffold using the CuAAC reaction and using long and hydrophilic ethylene glycol spacers. Initially, two galactosylcalix[4]arenes were prepared starting from saccharide units and calixarene cores which differ in the relative dispositions of the alkyne and azido groups. Once the most convenient synthetic pathway was selected, two further lactosylcalix[4]arenes were obtained, one in the cone, the other one in the 1,3-alternate structure. Preliminary studies of the interactions of these novel glycocalixarenes with galectin-3 were carried out by using a lectin-functionalized chip and surface plasmon resonance. These studies indicate a higher affinity of lactosyl- over galactosylcalixarenes. Furthermore, we confirmed that in case of this specific lectin binding the presentation of lactose units on a cone calixarene is highly preferred with respect to its isomeric form in the 1,3-alternate structure.