Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies

Pillaiyar Thanigaimalai, Sho Konno, Takehito Yamamoto, Yuji Koiwai, Akihiro Taguchi, Kentaro Takayama, Fumika Yakushiji, Kenichi Akaji, Shen En Chen, Aurash Naser-Tavakolian, Arne Schön, Ernesto Freire, Yoshio Hayashi

Research output: Contribution to journalArticlepeer-review

Abstract

We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.

Original languageEnglish (US)
Pages (from-to)372-384
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume68
DOIs
StatePublished - 2013

Keywords

  • Cysteine protease inhibitors
  • Dipeptide
  • Peptidomimetics
  • SARS

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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