Toward an HDAC6 inhibitor: synthesis and conformational analysis of cyclic hexapeptide hydroxamic acid designed from alpha-tubulin sequence.
A cyclic hexapeptide hydroxamic acid inhibitor for HDAC6 has been designed and synthesized on the basis of the facts that alpha-tubulin is the substrate of HDAC6 and of the excellent inhibitory activity of cyclic tetrapeptide hydroxamic acids (CHAPs) for HDACs. Unexpectedly, cyclic hexapeptide hydroxamic acid showed very low HDAC inhibitory activity. To explain the low activity, we have carried out conformation analysis and compared it to the crystal structure of alpha-tubulin. The conformation around the acetylated lysine of the cyclic hexapeptide substrate or the aminosuberate hydroxamic acid [Asu(NHOH)] of cyclic hexapeptide inhibitor is different from that around alpha-tubulin's lysine-40. The difference in the conformation seems to cause some steric hindrance at the capping site resulting in poor binding capacity.
Jose
Binoy
B
CREST Research Project, Japan Science and Technology Agency, Saitama 332-001, Japan.
Okamura
Shinji
S
Kato
Tamaki
T
Nishino
Norikazu
N
Sumida
Yuko
Y
Yoshida
Minoru
M
D000107:Acetylation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D008239:Lysine