ABSTRACT
We have designed and synthesized a helical cysteamine-terminated oligourea foldamer composed of ten urea residues featuring side carboxyl and amine groups. The carboxyl group is located in proximity to the C-terminus of the oligourea and hence at the negative pole of the helix dipole. The amine group is located close to the N-terminus and hence at the positive pole of the helix dipole. Beyond the already remarkable dipole moment inherent in oligourea 2.5 helices, the incorporation of additional charges originating from the carboxylic and amine groups is supposed to impact the overall charge distribution along the molecule. These molecules were self-assembled into monolayers on a gold substrate, allowing us to investigate the influence of an electric field on these polar helices. By applying surface-enhanced infrared reflection-absorption spectroscopy, we proved that molecules within the monolayers tend to reorient themselves more vertically when a negative bias is applied to the surface. It was also found that surface-confined oligourea molecules affected by the external electric field tend to rearrange the electron density at urea groups, leading to the stabilization of the resonance structure with charge transfer character. The presence of the external electric field also affected the nanomechanical properties of the oligourea films, suggesting that molecules also tend to reorient in the ambient environment without an electrolyte solution. Under the same conditions, the helical oligourea displayed a robust piezoresponse, particularly noteworthy given the slender thickness of the monolayer, which measured approximately 1.2 nm. This observation demonstrates that thin molecular films composed of oligoureas may exhibit stimulus-responsive properties. This, in turn, may be used in nanotechnology systems as actuators or functional films, enabling precise control of their thickness in the range of even fractions of nanometers.
ABSTRACT
Plasmodium multi-resistance, including against artemisinin, seriously threatens malaria treatment and control. Hence, new drugs are urgently needed, ideally targeting different parasitic stages, which are not yet targeted by current drugs. The SUB1 protease is involved in both hepatic and blood stages due to its essential role in the egress of parasites from host cells, and, as potential new target, it would meet the above criteria. We report here the synthesis as well as the biological and structural evaluation of substrate-based α-ketoamide SUB1 pseudopeptidic inhibitors encompassing positions P4-P2'. By individually substituting each position of the reference compound 1 (MAM-117, Ac-Ile-Thr-Ala-AlaCO-Asp-Glu (Oall)-NH2), we better characterized the structural determinants for SUB1 binding. We first identified compound 8 with IC50 values of 50 and 570 nM against Pv- and PfSUB1, respectively (about 3.5-fold higher potency compared to 1). Compound 8 inhibited P. falciparum merozoite egress in culture by 37% at 100 µM. By increasing the overall hydrophobicity of the compounds, we could improve the PfSUB1 inhibition level and antiparasitic activity, as shown with compound 40 (IC50 values of 12 and 10 nM against Pv- and PfSUB1, respectively, IC50 value of 23 µM on P. falciparum merozoite egress). We also found that 8 was highly selective towards SUB1 over three mammalian serine peptidases, supporting the promising value of this compound. Finally, several crystal 3D-structures of SUB1-inhibitor complexes, including with 8, were solved at high resolution to decipher the binding mode of these compounds.