2. Academic Validation
  3. Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome

Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome

  • Bioorg Med Chem Lett. 2005 Apr 1;15(7):1867-71. doi: 10.1016/j.bmcl.2005.02.013.
Isao Momose 1,  Yoji Umezawa,  Sehei Hirosawa,  Hironobu Iinuma,  Daishiro Ikeda
Affiliations

Affiliation

  • 1 Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, 18-24 Miyamoto, Numazu City, Shizuoka 410-0301, Japan. [email protected]
PMID: 15780623 DOI: 10.1016/j.bmcl.2005.02.013
Abstract

Tyropeptin A, a new potent Proteasome Inhibitor, was produced by Kitasatospora sp. MK993-dF2. To enhance the inhibitory potency of tyropeptin A, we constructed the structural model of tyropeptin A bound to the site responsible for the chymotrypsin-like activity of mammalian 20S Proteasome. Based on these modeling experiments, we designed and synthesized several derivatives of tyropeptin A. Among them, the most potent compound, TP-104, exhibited a 20-fold enhancement in its inhibitory potency compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the PGPH and the trypsin-like activities.

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