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Cyclative cleavage of an amine-carbamate self-immolative spacer to deliver a hydroxyl cargo was inhibited by spacer derivatisation with a phosphate monoester handle. This trifunctional spacer was installed in a model anticancer prodrug that showed fast drug release only when incubated with both a protease and a phosphatase enzyme. [ABSTRACT FROM AUTHOR]

DC-SIGN antagonists were designed combining one selective monovalent glycomimetic ligand with trivalent dendrons separated by a rigid core of controlled length. The design combines multiple multivalency effects to achieve inhibitors of HIV infection, which are active in nanomolar concentration. [ABSTRACT FROM AUTHOR]

NMR experiments (transferred NOE and Saturation Transfer Difference) were used to shed light on the binding epitope of RGD peptidomimetics 1-3 with integrins αvβ3 and α(IIb)β3, expressed on the membrane of ECV304 bladder cancer cells and human platelets, respectively. The NMR results were supported by docking calculations of 1-3 in the active sites of αvβ3 and α(IIb)β3 integrin receptors and were compared to the results of competitive αvβ3 receptor binding assays and competitive ECV304 cell adhesion experiments. While cis RGD ligand 1 interacts mainly with the α integrin subunit through its basic guanidine group, trans RGD ligands 2 and 3 are able to interact with both the α and β integrin subunits via an electrostatic clamp.

In this paper we report an extensive NMR analysis of small ligands (Smac mimics) complexed with different constructs of XIAP. The mimics-binding site of XIAP is known as the BIR3 domain - primary, and the linker BIR2 region - secondary site. Interactions between the BIR3 domain and Smac mimics have been extensively studied by X-ray but, as of today, there are scarce data about the interaction between BIR2, or the whole linker-BIR2-BIR3 construct, and Smac mimics. In order to characterize our Smac mimics, we performed a STD NMR study between our 4-substituted, 1-aza-2-oxobicyclo[5.3.0]decane scaffold-based molecules and three different XIAP fragments: single BIR2 and BIR3 domains, and bifunctional linker-BIR2-BIR3. The results were integrated with docking calculations and molecular dynamics simulations. NMR data, which are consistent with biological tests, indicated that the two BIR subunits interact differently with our Smac mimics and suggest that the ligands enter into more intimate contact with the linker-BIR2-BIR3. In conclusion, we observe that the SMAC mimics showed with the construct linker-BIR2-BIR3 a series of NOE contacts that were not observed in the mono-domain ligand:BIR2 or :BIR3 complexes. So, in agreement with the computational models we believe that the linker moieties of the binding site play a key role in the stability of the protein complex., (This journal is © The Royal Society of Chemistry 2012)

DC-SIGN and Langerin are two C-type lectins involved in the initial steps of HIV infections: the former acts as a viral attachment factor and facilitates viral invasion of the immune system, the latter has a protective effect. Potential antiviral compounds targeted against DC-SIGN were synthesized using a common fucosylamide anchor. Their DC-SIGN affinity was tested by SPR and found to be similar to that of the natural ligand Lewis-X (Le(X)). The compounds were also found to be selective for DC-SIGN and to interact only weakly with Langerin. These molecules are potentially useful therapeutic tools against sexually transmitted HIV infection.

The aim of this work is to show that transferred-NOE provides useful and detailed information on membrane-bound receptor-ligand interactions in living cells. Here, we study the interaction between intact human platelets and some ligands containing the RGD sequence. Conformational properties of the free and bound pentapeptides are reported.