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We recently showed that solid-phase peptide synthesis using racemic amino acids yields stereorandomized peptides comprising all possible diastereomers as homogeneous, single-mass products that can be purified by HPLC and that stereorandomization modulates activity, toxicity, and stability of membrane-disruptive cyclic and linear antimicrobial peptides (AMPs) and dendrimers. Here, we tested if stereorandomization might be compatible with target binding peptides with the example of the proline-rich AMP oncocin, which inhibits the bacterial ribosome. Stereorandomization of up to nine C-terminal residues preserved ribosome binding and antibacterial effects including activities against drug-resistant bacteria and protected against serum degradation. Surprisingly, fully stereorandomized oncocin was as active as L-oncocin in dilute growth media stimulating peptide uptake, although it did not bind the ribosome, indicative of an alternative mechanism of action. These experiments show that stereorandomization can be compatible with target binding peptides and can help understand their mechanism of action.

Membrane disruptive α-helical antimicrobial peptides (AMPs) offer an opportunity to address multidrug resistance; however, most AMPs are toxic and unstable in serum. These limitations can be partly overcome by introducing D-residues, which often confers protease resistance and reduces toxicity without affecting antibacterial activity, presumably due to lowered α-helicity. Here, we investigated 31 diastereomers of the α-helical AMP KKLLKLLKLLL. Three diastereomers containing two, three, and four D-residues showed increased antibacterial effects, comparable hemolysis, reduced toxicity against HEK293 cells, and excellent serum stability, while another diastereomer with four D-residues additionally displayed lower hemolysis. X-ray crystallography confirmed that high or low α-helicity as measured by circular dichroism indicated α-helical or disordered structures independently of the number of chirality switched residues. In contrast to previous reports, α-helicity across diastereomers correlated with both antibacterial activity and hemolysis and revealed a complex relationship between stereochemistry, activity, and toxicity, highlighting the potential of diastereomers for property optimization.

L’insomnie chronique est un problème de santé majeur avec une prévalence pouvant atteindre 50 % en soin courant. Le traitement de première intention recommandé est la thérapie cognitive et comportementale pour l’insomnie (TCCi), malheureusement peu accessible. La digitalisation offre la possibilité de réduire les inégalités d’accès aux soins en proposant des options de soins plus flexibles et accessibles. De plus, la TCCi numérique s’est avérée aussi efficace que la TCCi en personne. Cependant, comme pour les soins traditionnels, une approche basée sur des preuves et l’engagement des patients demeure fondamentale. Objectif Développement d’un programme de TCCi numérique basé sur des connaissances théoriques et cliniques, et pensé pour être efficacement mis en œuvre dans le système de santé.

•Two main strategies are commonly used for p-PBPK models building.•More and more time-varying parameters specific to pregnancy in PBPK models.•Data required to better characterize placental transfers and fetal distribution.•p-PBPK models are key tools for fetal exposure assessment in a DOHaD context.