Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety

Sho Konno, Pillaiyar Thanigaimalai, Takehito Yamamoto, Kiyohiko Nakada, Rie Kakiuchi, Kentaro Takayama, Yuri Yamazaki, Fumika Yakushiji, Kenichi Akaji, Yoshiaki Kiso, Yuko Kawasaki, Shen En Chen, Ernesto I Freire, Yoshio Hayashi

Research output: Contribution to journalArticle

Abstract

We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CLpro. A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CLpro motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1′ site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC50 or K i values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K i values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CLpro may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1′-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.

Original languageEnglish (US)
Pages (from-to)412-424
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number2
DOIs
StatePublished - Jan 15 2013

Fingerprint

SARS Virus
Peptidomimetics
Protease Inhibitors
Lead compounds
Thiazoles
Lactams
Stereochemistry
Hydrogen Bonding
Inhibitory Concentration 50
Conformations
Hydrogen bonds
Derivatives
Molecules
benzothiazole
Therapeutics

Keywords

  • Cysteine protease inhibitors
  • Docking study
  • Peptidomimetics
  • SARS
  • SARS-CoV 3CL protease

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety. / Konno, Sho; Thanigaimalai, Pillaiyar; Yamamoto, Takehito; Nakada, Kiyohiko; Kakiuchi, Rie; Takayama, Kentaro; Yamazaki, Yuri; Yakushiji, Fumika; Akaji, Kenichi; Kiso, Yoshiaki; Kawasaki, Yuko; Chen, Shen En; Freire, Ernesto I; Hayashi, Yoshio.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 2, 15.01.2013, p. 412-424.

Research output: Contribution to journalArticle

Konno, S, Thanigaimalai, P, Yamamoto, T, Nakada, K, Kakiuchi, R, Takayama, K, Yamazaki, Y, Yakushiji, F, Akaji, K, Kiso, Y, Kawasaki, Y, Chen, SE, Freire, EI & Hayashi, Y 2013, 'Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety', Bioorganic and Medicinal Chemistry, vol. 21, no. 2, pp. 412-424. https://doi.org/10.1016/j.bmc.2012.11.017
Konno, Sho ; Thanigaimalai, Pillaiyar ; Yamamoto, Takehito ; Nakada, Kiyohiko ; Kakiuchi, Rie ; Takayama, Kentaro ; Yamazaki, Yuri ; Yakushiji, Fumika ; Akaji, Kenichi ; Kiso, Yoshiaki ; Kawasaki, Yuko ; Chen, Shen En ; Freire, Ernesto I ; Hayashi, Yoshio. / Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 2. pp. 412-424.
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