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Drug targeting is a methodology that helps to overcome the side effects of therapeutic molecules. However, insufficient targeting specificity and the on-target/off-site delivery leave much room for improvement in the targeting endeavors. One approach to enhance the specificity of drug targeting is to engineer artificial receptors with recognition ligands not observed in nature. To this end, artificial internalizing receptors that feature cholesterylamine as the artificial pull-in mechanism, and an anti-fluorescein antibody as the exofacial recognition and capture tool are developed. Fluorescein labeling is among the most routine techniques in biochemistry and can readily provide a way to make cognate derivatives for receptor-mediated endocytosis using these artificial receptors. Herein, the synthesis and the structure-activity relationship for these artificial receptors are detailed, their potency and efficacy in mediating drug delivery for the antibody-drug conjugates are illustrated, and the scope and limitations of targeting the chemically engineered cells via artificial receptors are investigated. Taken together, the presented data explore an innovative approach to drug targeting and contribute to the development of techniques in cell engineering using the tools of chemistry., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Peptides are prime drug candidates due to their high specificity of action but are disadvantaged by low proteolytic stability. Here, we focus on the development of stabilized analogues of EPI-X4, an endogenous peptide antagonist of CXCR4. We synthesized macromolecular peptide conjugates and performed side-by-side comparison with their albumin-binding counterparts and considered monovalent conjugates, divalent telechelic conjugates, and Y-shaped peptide dimers. All constructs were tested for competition with the CXCR4 antibody-receptor engagement, inhibition of receptor activation, and inhibition of the CXCR4-tropic human immunodeficiency virus infection. We found that the Y-shaped conjugates were more potent than the parent peptide and at the same time more stable in human plasma, with a favorable outlook for translational studies.

A high-yielding palladium-catalyzed C-S cross-coupling is presented for utilization in carbohydrate chemistry as a key transformation for attachment of a second chelating sulfur atom that allows the exploitation of a latent-active glycosylation strategy with Cu(OTf) 2 as the promoter. The novel approach employs o -Br-benzyl thioglycosides as latent glycosyl donors and o -SMe-benzyl thioglycosides as the active counterparts.

Gaseous fluorescein monoanions are weakly fluorescent; they display a broad fluorescence spectrum and a large Stokes shift. This contrasts with the situation in aqueous solution. One explanation of the intriguing behavior in vacuo is based on internal proton transfer from the pendant carboxyphenyl group to one of the xanthene oxygens in the excited state; another that rotation of the carboxyphenyl group relative to the xanthene leads to a partial charge transfer from one chromophore (xanthene) to the other (carboxyphenyl) when the π orbitals start to overlap. To shed light on the mechanism at play, we synthesized two fluorescein derivatives where the carboxylic acid group is replaced with either an ester or a tertiary amide functionality and explored their gas-phase ion fluorescence using the home-built LUminescence iNstrument in Aarhus (LUNA) setup. Results on the fluorescein methyl ester that has no acidic proton clearly disprove the former explanation: The spectrum remains broad, and the band center (at 605 nm) is shifted even more to the red than that of fluorescein (590 nm). Experiments on the other variant that contains a piperidino amide are also in favor of the second explanation as here the piperidino already causes the dihedral angle between the planes defining the xanthene and the benzene ring to be less than 90° in the ground state (i.e., 63°), according to density functional theory calculations. As a result of the closer similarity between the ground-state and excited-state structures, the fluorescence spectrum is narrower than those of the other two ions, and the band maximum is further to the blue (575 nm). In accordance with a more delocalized ground state of the amide derivative, action spectra associated with photoinduced dissociation recorded at another setup show that the absorption-band maximum for the amide derivative is redshifted compared to that of fluorescein (538 nm vs. 525 nm).