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Chem Pharm Bull (Tokyo). 2019 Oct 3. doi: 10.1248/cpb.c19-00634. [Epub ahead of print]

Structure-Activity Relationship Study on Col-003, a Protein-Protein Interaction Inhibitor between Collagen and Hsp47.

Author information

1
Graduate School of Pharmaceutical Science, Tohoku University.
2
Institute for Protein Dynamics, Kyoto Sangyo University.
3
National Institute of Advanced Industrial Science and Technology (AIST).
4
Graduate School of Life Sciences, Tohoku University.

Abstract

This study demonstrates the structure-activity relationship of Col-003, a potent collagen-heat-shock protein 47 (Hsp47) interaction inhibitor. Col-003 analogues were successfully synthesized by Pd(0)-catalyzed cross-coupling reactions of 5-bromosalicylaldehyde derivatives with alkyl-metal species, and the inhibitory activities of the synthetic analogues were evaluated using surface plasmon resonance analysis (BIAcore). We succeeded in discovering two potent inhibitors that showed 85% and 81% inhibition at a concentration of 1.9 μM against the collagen-Hsp47 interaction. This indicates that elongation of an alkyl linker between two aromatic rings could considerably improve inhibitory activity due to the adjustment of a pendant phenyl moiety to an appropriate position, in addition to the hydrophobic interaction with an alkyl linker moiety.

KEYWORDS:

collagen; heat-shock protein 47; protein–protein interaction; small-molecule inhibitor

PMID:
31582590
DOI:
10.1248/cpb.c19-00634
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