X-Ray Conformation and Structure-Activity Relationships of MA026, a Reversible Tight Junction Opener.

Autor:	Mukaiyama M; Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan., Uchiyama C; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Fukuda A; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Nakazawa Y; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Kuramochi Y; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Shibata Y; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Konno S; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Muguruma K; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Matsugaki N; Structural Biology Research Center, High Energy Accelerator Research Organization (KEK), Institute of Materials Structure Science, Tsukuba, Ibaraki 305-0801, Japan.; Department of Materials Structure Science, School of High Energy Accelerator Science, The Graduate University of Advanced Studies (Soken-dai), 1-1 Oho, Tsukuba, Tsukuba, Ibaraki 305-0801, Japan., Asari T; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Ogawa K; Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan., Taguchi A; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Takayama K; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Taniguchi A; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Nagumo Y; Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Institute of Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan., Senda T; Institute of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Structural Biology Research Center, High Energy Accelerator Research Organization (KEK), Institute of Materials Structure Science, Tsukuba, Ibaraki 305-0801, Japan.; Department of Materials Structure Science, School of High Energy Accelerator Science, The Graduate University of Advanced Studies (Soken-dai), 1-1 Oho, Tsukuba, Tsukuba, Ibaraki 305-0801, Japan., Hayashi Y; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan., Usui T; Institute of Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Microbiology Research Center for Sustainability (MiCS), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Jul 13; Vol. 66 (13), pp. 8717-8724. Date of Electronic Publication: 2023 Jun 23.
DOI:	10.1021/acs.jmedchem.3c00365
Abstrakt:	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.
Databáze:	MEDLINE
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