1. A Selective Cyclic Peptidic Human SIRT5 Inhibitor
Jiajia Liu, Yajun Huang, Weiping Zheng Molecules. 2016 Sep 10;21(9):1217. doi: 10.3390/molecules21091217.
In the current study, we discovered that a side chain-to-side chain cyclic pentapeptide harboring a central N(ε)-carboxyethyl-thiocarbamoyl-lysine residue behaved as a strong and selective (versus human SIRT1/2/3/6) inhibitor against human SIRT5-catalyzed deacylation reaction. This compound was also found to be proteolytically much more stable than its linear counterpart. This compound could be a valuable lead for developing stronger, selective, metabolically stable, and cell permeable human SIRT5 inhibitors.
2. A cyclic KLVFF-derived peptide aggregation inhibitor induces the formation of less-toxic off-pathway amyloid-β oligomers
Tadamasa Arai, Daisuke Sasaki, Takushi Araya, Takeshi Sato, Youhei Sohma, Motomu Kanai Chembiochem. 2014 Nov 24;15(17):2577-83. doi: 10.1002/cbic.201402430. Epub 2014 Sep 26.
Inhibition of amyloid-β (Aβ) aggregation could be a target of drug development for the treatment of currently incurable Alzheimer's disease. We previously reported that a head-to-tail cyclic peptide of KLVFF (cyclic-KLVFF), a pentapeptide fragment corresponding to the Aβ16-20 region (which plays a critical role in the generating Aβ fibrils), possesses potent inhibitory activity against Aβ aggregation. Here we found that the inhibitory activity of cyclic-KLVFF was significantly improved by incorporating an additional phenyl group at the β-position of the Phe4 side chain (inhibitor 3). Biophysical and biochemical analyses revealed the rapid formation of 3-embedded oligomer species when Aβ1-42 was mixed with 3. The oligomer species is an "off-pathway" species with low affinity for cross-β-sheet-specific dye thioflavin T and oligomer-specific A11 antibodies. The oligomer species had a sub-nanometer height and little capability of aggregation to amyloid fibrils. Importantly, the toxicity of the oligomer species was significantly lower than that of native Aβ oligomers. These insights will be useful for further refinement of cyclic-KLVFF-based aggregation inhibitors.
3. Cyclic pentapeptide endothelin A receptor antagonists with attenuated in vivo clearance
T Fukami, K Niiyama, Y Amano, A Hisaka, N Fujino, Y Sawasaki, M Ihara, K Ishikawa Chem Pharm Bull (Tokyo). 1996 Mar;44(3):609-14. doi: 10.1248/cpb.44.609.
A series of analogues of BQ-123 (1), a potent cyclic pentapeptide endothelin A receptor antagonist, with amino acids linked to the side-chain of the Pro residue via an ester linkage was synthesized. All analogues synthesized exhibited potent endothelin A receptor binding affinity similar to that of 1. Of the synthesized analogues, the Lys, Arg and N alpha,N epsilon-dimethyllysine analogues, 9d-f, exhibited about a three-fold attenuation of in vivo clearance compared with 1. In rats, these analogues exhibited a 3-fold-higher plasma concentration and a longer retention time in plasma as compared with those of 1. The attenuated in vivo clearance was thought to be a consequence of decreased extraction of the compounds from the blood via the hepatic anion transport system, which efficiently extracts 1 from the blood.
