3 research outputs found
(<i>S</i>)ā<i>N</i>āMethyldihydroquinazolinones are the Active Enantiomers of Retroā2 Derived Compounds against Toxins
This
study reports the synthesis, chromatographic separation, and
pharmacological evaluation of the two enantiomers of a new compound,
named Retro-2.1, active against toxins by inhibiting intracellular
trafficking via the retrograde route. The absolute configuration of
the bioactive enantiomer has been assigned from X-ray diffraction
to the (<i>S</i>)-enantiomer. To date, (<i>S</i>)-Retro-2.1 is the most potent molecule to counteract the cytotoxic
potential of ricin and Shiga toxin, with EC50 values of 23 and 54
nM, respectively
<i>N</i>āMethyldihydroquinazolinone Derivatives of Retroā2 with Enhanced Efficacy against Shiga Toxin
The
Retro-2 molecule protects cells against Shiga toxins by specifically
blocking retrograde transport from early endosomes to the trans-Golgi
network. A SAR study has been carried out to identify more potent
compounds. Cyclization and modifications of Retro-2 led to a compound
with roughly 100-fold improvement of the EC<sub>50</sub> against Shiga
toxin cytotoxicity measured in a cell protein synthesis assay. We
also demonstrated that only one enantiomer of the dihydroquinazolinone
reported herein is bioactive
Structural Role of Counterions Adsorbed on Self-Assembled Peptide Nanotubes
Among noncovalent forces, electrostatic ones are the
strongest
and possess a rather long-range action. For these reasons, charges
and counterions play a prominent role in self-assembly processes in
water and therefore in many biological systems. However, the complexity
of the biological media often hinders a detailed understanding of
all the electrostatic-related events. In this context, we have studied
the role of charges and counterions in the self-assembly of lanreotide,
a cationic octapeptide. This peptide spontaneously forms monodisperse
nanotubes (NTs) above a critical concentration when solubilized in
pure water. Free from any screening buffer, we assessed the interactions
between the different peptide oligomers and counterions in solutions,
above and below the critical assembly concentration. Our results provide
explanations for the selection of a dimeric building block instead
of a monomeric one. Indeed, the apparent charge of the dimers is lower
than that of the monomers because of strong chemisorption. This phenomenon
has two consequences: (i) the dimerādimer interaction is less
repulsive than the monomerāmonomer one and (ii) the lowered
charge of the dimeric building block weakens the electrostatic repulsion
from the positively charged NT walls. Moreover, additional counterion
condensation (physisorption) occurs on the NT wall. We furthermore
show that the counterions interacting with the NTs play a structural
role as they tune the NTs diameter. We demonstrate by a simple model
that counterions adsorption sites located on the inner face of the
NT walls are responsible for this size control