Study on Medicinal Chemistry of Reversible Cysteine Protease Inhibitors for the Treatment of Infectious Diseases

2012 Fiscal Year Final Research Report

• Project/Area Number: 23659059
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: HAYASHI Yoshio 東京薬科大学, 薬学部, 教授 (10322562)
• Project Period (FY): 2011 – 2012
• Keywords: 医薬品化学 / 創薬化学 / プロテアーゼ阻害剤 / 重症急性呼吸器症候群 / ビオチニル化試薬 / 感染症 / 固相合成化学 / システインプロテアーゼ

Research Abstract

This work describes the establishment of common method for the development of cysteine protease inhibitors based on the aryl-ketone structure. As an example, from our preliminary inhibitor with a mild activity, we developed potent tri- and di-peptide-type SARS-CoV 3CL protease inhibitors. The results suggested that our aryl-ketone strategy worked effectively in the development of viral cysteine protease inhibitors. In addition, we developed a solid phase reagent that can introduce biotin to the target molecules by a very simple procedure in order to obtain a high affinity substrate, which can be changeable to the potent inhibitor by introducing the aryl-ketone structure.

Research Products

• [Journal Article] Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety (2013)
  • Author(s): Sho Konno, Thanigaimalai Pillaiyar, Takehito Yamamoto, Kiyohiko Nakada, Rie Kakiuchi, Kentaro Takayama, Yuri Yamazaki, Fumika Yakushiji, Kenichi Akaji, Yoshiaki Kiso, Yuko Kawasaki, Shen-En Chen, Ernesto Freire,Yoshio Hayashi
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 21(2) Pages: 412-424
  • DOI: DOI:org/10.1016/j.bmc.2012.11.017
• [Journal Article] Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure-activity relationship study (2013)
  • Author(s): Pillaiyar Thanigaimalai, Sho Konno, Takehito Yamamoto, Yuji Koiwai, Kentaro Takayama,Fumika Yakushiji, Kenichi Akaji, Yuko Kawasaki, Shen-En Chen, Aurash NaserTavakolian, Arne Schon, Ernesto Freire,Yoshio Hayashi
  • Journal Title: Eur. J. Med. Chem Volume: 65 Pages: 436-447
  • DOI: DOI:org/10.1016/j.ejmech.2013.05.005
• [Journal Article] Development of a solidsupported biotinylation reagent for efficient biotin labeling of SH groups on small molecules (2012)
  • Author(s): Kentarou Fukumoto, Kumi Adachi, Akihiro Kajiyama, Yuri Yamazaki, Fumika Yakushiji, Yoshio Hayashi
  • Journal Title: Tetrahedron Lett Volume: 53 Pages: 535-538
  • DOI: DOI:org/10.1016/j.tetlet.2011.11.089
• [Presentation] Development of tripeptide-type SARS coronavirus 3CL protease inhibitors with an electrophilic 2-benzothiazole ketone structure (2012)
  • Author(s): Takehito Yamamoto
  • Organizer: 244th ACS National Meeting & Exposition
  • Place of Presentation: Philadelphia, PA, United States
  • Year and Date: 20120819-23
• [Presentation] Peptidic cysteine protease inhibitors with an arylketone warhead for SARS Coronavirus (2012)
  • Author(s): Sho Konno
  • Organizer: PEM6 (6th Peptide Engineering Meeting)
  • Place of Presentation: Atlanta, Georgia, UAS
  • Year and Date: 2012-10-02
• [Presentation] The development of tripeptide-type SARS Coronavirus 3CLprotease inhibitors: Structure-activity relationships at P4 moiety (2012)
  • Author(s): Takehito Yamamoto
  • Organizer: The Pharmaceutical Society of Japan
  • Place of Presentation: Sapparo, Japan
  • Year and Date: 2012-03-29
• [Presentation] Development of SARS Coronovirus 3CL protease inhibitors with an electrophilic arylketone structure (2011)
  • Author(s): Sho Konno
  • Organizer: 8^<th> AFMC International Medicinal Chemistry Symposium
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2011-10-01
• [Presentation] Design, Synthesis and Evaluation of Tripeptidomimetics with arylketone as inhibitors of SARS-CoV 3CL Protease (2011)
  • Author(s): Sho Konno
  • Organizer: 48^<th> Japanese Peptide Symposium
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2011-09-28
• [Remarks]
  • URL: http://hinka-toyaku.s2.weblife.me/index.html