Biomedical subjects

Nicoleta Kokkoni

Publications and source records attributed to Nicoleta Kokkoni.

3 recordsLinked to original sources

PubMed2006

N-Methylated peptide inhibitors of beta-amyloid aggregation and toxicity. Optimization of the inhibitor structure.

The key pathogenic event in the onset of Alzheimer's disease (AD) is believed to be the aggregation of the beta-amyloid (Abeta) peptide into toxic oligomers. Molecules that interfere with this process may therefore act as therapeutic agents for the treatment of AD. N-Methylated peptides (meptides) are a general class of peptide aggregation inhibitors that act by binding to one face of the aggregating peptide but are unable to hydrogen bond on the other face, because of the N-methyl group replacing a backbone NH group. Here, we optimize the structure of meptide inhibitors of Abeta aggregation, starting with the KLVFF sequence that is known to bind to Abeta. We varied the meptide length, N-methylation sites, acetylation, and amidation of the N and C termini, side-chain identity, and chirality, via five compound libraries. Inhibitor activity was tested by thioflavin T binding, affinity chromatography, electron microscopy, and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide toxicity assay. We found that inhibitors should have all d chirality, have a free N terminus but an amidated C terminus, and have large, branched hydrophobic side chains at positions 1-4, while the side chain at position 5 was less important. A single N-methyl group was necessary and sufficient. The most active compound, d-[(chGly)-(Tyr)-(chGly)-(chGly)-(mLeu)]-NH(2), was more active than all previously reported peptide inhibitors. Its related non-N-methylated analogues were insoluble and toxic.

Amino Acid Sequence↗

PubMed2003

Design strategies for anti-amyloid agents.

Numerous diseases have been linked to a common pathogenic process called amyloidosis, whereby proteins or peptides clump together in the brain or body to form toxic soluble oligomers and/or insoluble fibres. An attractive strategy to develop therapies for these diseases is therefore to inhibit or reverse protein/peptide aggregation. A diverse range of small organic ligands have been found to act as aggregation inhibitors. Alternatively, the wild-type peptide can be derivatised so that it still binds to the amyloid target, but prevents further aggregation. This can be achieved by adding a bulky group or charged amino acid to either end of the peptide, or by incorporating proline residues or N-methylated amide groups.

Amyloid beta-Peptides↗

PubMed2002

Stabilizing interactions between aromatic and basic side chains in alpha-helical peptides and proteins. Tyrosine effects on helix circular dichroism.

Here we investigate the structures and energetics of interactions between aromatic (Phe or Tyr) and basic (Lys or Arg) amino acids in alpha-helices. Side chain interaction energies are measured using helical peptides, by quantifying their helicities with circular dichroism at 222 nm and interpreting the results with Lifson-Roig-based helix/coil theory. A difficulty in working with Tyr is that the aromatic ring perturbs the CD spectrum, giving an incorrect helicity. We calculated the effect of Tyr on the CD at 222 nm by deriving the intensities of the bands directly from the electronic and magnetic transition dipole moments through the rotational strengths corresponding to each excited state of the polypeptide. This gives an improved value of the helix preference of Tyr (from 0.48 to 0.35) and a correction to the helicity for the peptides containing Tyr. We find that Phe-Lys, Lys-Phe, Phe-Arg, Arg-Phe, and Tyr-Lys are all stabilizing by -0.10 to -0.18 kcal.mol-1 when placed i, i + 4 on the surface of a helix in aqueous solution, despite the great difference in polarity between these residues. Interactions between these side chains have previously been attributed to cation-pi bonds. A survey of protein structures shows that they are in fact predominantly hydrophobic interactions between the CH2 groups of Lys or Arg and the aromatic rings.

Amino Acid Sequence↗