Q1 · MEDICINE
Article
Author: Taniguchi, Atsuhiko ; Senda, Toshiya ; Nagumo, Yoko ; Usui, Takeo ; Konno, Sho ; Shibata, Yudai ; Nakazawa, Yoshiki ; Muguruma, Kyohei ; Taguchi, Akihiro ; Fukuda, Akane ; Uchiyama, Chihiro ; Hayashi, Yoshio ; Kuramochi, Yuka ; Asari, Tomo ; Ogawa, Kazuyoshi ; Takayama, Kentaro ; Matsugaki, Naohiro ; Mukaiyama, Minagi
MA026, a cyclic lipodepsipeptide, opens the tight junction (TJ) probably via binding to claudin-1. We reported that (1) TJ-opening activity is dependent on the amino acid sequence order at Glu10-Leu11; (2) an epimer at the C3 position of the N-terminal acyl tail decreased the TJ-opening activity; and (3) the epimers D-Leu1/L-Gln6 and L-Leu1/D-Gln6 showed more potent TJ-opening activity than natural MA026, although no systematic structure-activity relationship (SAR) study was conducted. Here, we report the three-dimensional structure and systematic SAR study of MA026. X-Ray crystallography and circular dichroism analysis of MA026 revealed that MA026 forms a left-handed α-helical structure, and hydrophobic amino acids are clustered on one side. Furthermore, the SAR results clearly showed that the hydrophobic region of MA026 is important for TJ-opening activity. These results suggest that MA026 interacts with claudin-1 via the hydrophobic cluster region and provide novel structural insights toward the development of a TJ opener targeting claudin-1.