Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors.

Abstract

With the aim of discovering potent and selective dengue NS3 protease inhibitors, we systematically synthesized and evaluated a series of tetrapeptide aldehydes based on lead aldehyde 1 (Bz-Nle-Lys-Arg-Arg-H, K(i)=5.8 microM). In general, we observe that interactions of P(2) side chain are more important than P(1) followed by P(3) and P(4). Tripeptide and dipeptide aldehyde inhibitors also show low micromolar activity. Additionally, an effective non-basic, uncharged replacement of P(1) Arg is identified.

• Authors: Zheng Yin, Sejal J Patel, Wei-Ling Wang, Wai-Ling Chan, K R Ranga Rao, Gang Wang, Xinyi Ngew, Viral Patel, David Beer, John E Knox, Ngai Ling Ma, Claus Ehrhardt, Siew Pheng Lim, Subhash G Vasudevan, Thomas H Keller
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 16 Issue 1 Pg. 40-3 (Jan 01 2006) ISSN: 0960-894X [Print] England
• PMID: 16246563 (Publication Type: Journal Article)

Chemical References

• Aldehydes
• Boronic Acids
• Enzyme Inhibitors
• Ketones
• NS3 protein, flavivirus
• Peptides
• Protease Inhibitors
• Viral Nonstructural Proteins
• Serine Endopeptidases
• RNA Helicases

Topics

• Aldehydes (antagonists & inhibitors)
• Binding, Competitive
• Boronic Acids (chemistry)
• Chemistry, Pharmaceutical (methods)
• Dengue Virus (enzymology)
• Dose-Response Relationship, Drug
• Drug Design
• Enzyme Inhibitors (pharmacology)
• Hydrogen Bonding
• Ketones (chemistry)
• Kinetics
• Models, Chemical
• Models, Molecular
• Peptides (chemistry, pharmacology)
• Protease Inhibitors (chemistry, pharmacology)
• Protein Binding
• RNA Helicases (antagonists & inhibitors, chemistry)
• Serine Endopeptidases (chemistry)
• Structure-Activity Relationship
• Substrate Specificity
• Time Factors
• Viral Nonstructural Proteins (antagonists & inhibitors, chemistry)