2. Academic Validation
  3. Activators of cylindrical proteases as antimicrobials: identification and development of small molecule activators of ClpP protease

Activators of cylindrical proteases as antimicrobials: identification and development of small molecule activators of ClpP protease

  • Chem Biol. 2011 Sep 23;18(9):1167-78. doi: 10.1016/j.chembiol.2011.07.023.
Elisa Leung 1,  Alessandro Datti,  Michele Cossette,  Jordan Goodreid,  Shannon E McCaw,  Michelle Mah,  Alina Nakhamchik,  Koji Ogata,  Majida El Bakkouri,  Yi-Qiang Cheng,  Shoshana J Wodak,  Bryan T Eger,  Emil F Pai,  Jun Liu,  Scott Gray-Owen,  Robert A Batey,  Walid A Houry
Affiliations

Affiliation

  • 1 Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
PMID: 21944755 DOI: 10.1016/j.chembiol.2011.07.023
Abstract

ClpP is a cylindrical serine protease whose ability to degrade proteins is regulated by the unfoldase ATP-dependent chaperones. ClpP on its own can only degrade small Peptides. Here, we used ClpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five distinct compounds, which we designate as Activators of Self-Compartmentalizing Proteases 1 to 5 (ACP1 to 5). The compounds are found to stabilize the ClpP double-ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent classes of compounds that can activate ClpP and that can be developed as potential novel Antibiotics.

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