5 research outputs found
From a Marine Neuropeptide to Antimicrobial Pseudopeptides Containing Aza-β<sup>3</sup>-Amino Acids: Structure and Activity
Incorporation of aza-β<sup>3</sup>-amino acids
into an endogenous
neuropeptide from mollusks (ALSGDAFLRF-NH<sub>2</sub>) with weak antimicrobial
activity allows the design of new AMPs sequences. Depending on the
nature of the substitution, this can render the pseudopeptides inactive
or lead to a drastic enhancement of the antimicrobial activity without
high cytotoxicity. Structural studies of the pseudopeptides carried
out by NMR and circular dichroism show the impact of aza-β<sup>3</sup>-amino acids on peptide structure. The first three-dimensional
structures of pseudopeptides containing aza-β<sup>3</sup>-amino
acids in aqueous micellar SDS were determined and demonstrate that
the hydrazino turn can be formed in aqueous solution. Thus, AMP activity
can be modulated through structural modifications induced by the nature
and the position of such amino acid analogues in the peptide sequences
Revisiting Peptide Amphiphilicity for Membrane Pore Formation
It has previously been shown that an amphipathic de novo
designed peptide made of 10 leucines and four phenylalanines substituted
with crown ethers induces vesicle leakage without selectivity. To
gain selectivity against negatively charged dimyristoylphosphatidylglycerol
(DMPG) bilayers, one or two leucines of the peptide were substituted
with positively charged residues at each position. All peptides induce
significant calcein leakage of DMPG vesicles. However, some peptides
do not induce significant leakage of zwitterionic dimyristoylphosphatidylcholine
vesicles and are thus active against only bacterial model membranes.
The intravesicular leakage is induced by pore formation instead of
membrane micellization. Nonselective peptides are mostly helical,
while selective peptides mainly adopt an intermolecular β-sheet
structure. This study therefore demonstrates that the position of
the lysine residues significantly influences the secondary structure
and bilayer selectivity of an amphipathic 14-mer peptide, with β-sheet
peptides being more selective than helical peptides
Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne
The use of an interleukin β
antibody is currently being investigated in the clinic for the treatment
of acne, a dermatological disorder affecting 650M persons globally.
Inhibiting the protease responsible for the cleavage of inactive pro-IL1β
into active IL-1β, caspase-1, could be an alternative small
molecule approach. This report describes the discovery of uracil <b>20</b>, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor
for the topical treatment of inflammatory acne. The uracil series
was designed according to a published caspase-1 pharmacophore model
involving a reactive warhead in P1 for covalent reversible inhibition
and an aryl moiety in P4 for selectivity against the apoptotic caspases.
Reversibility was assessed in an enzymatic dilution assay or by using
different substrate concentrations. In addition to classical structure–activity-relationship
exploration, topical administration challenges such as phototoxicity,
organic and aqueous solubility, chemical stability in solution, and
skin metabolic stability are discussed and successfully resolved
A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.
Context: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). Objective: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. Design and Patients: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. Results: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. Conclusion: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations
Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne
The use of an interleukin β
antibody is currently being investigated in the clinic for the treatment
of acne, a dermatological disorder affecting 650M persons globally.
Inhibiting the protease responsible for the cleavage of inactive pro-IL1β
into active IL-1β, caspase-1, could be an alternative small
molecule approach. This report describes the discovery of uracil <b>20</b>, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor
for the topical treatment of inflammatory acne. The uracil series
was designed according to a published caspase-1 pharmacophore model
involving a reactive warhead in P1 for covalent reversible inhibition
and an aryl moiety in P4 for selectivity against the apoptotic caspases.
Reversibility was assessed in an enzymatic dilution assay or by using
different substrate concentrations. In addition to classical structure–activity-relationship
exploration, topical administration challenges such as phototoxicity,
organic and aqueous solubility, chemical stability in solution, and
skin metabolic stability are discussed and successfully resolved