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

• Published in: Bioorganic & medicinal chemistry letters 2006, Vol.16 (1), p.40-43
• Main Authors: Yin, Zheng, Patel, Sejal J., Wang, Wei-Ling, Chan, Wai-Ling, Ranga Rao, K.R., Wang, Gang, Ngew, Xinyi, Patel, Viral, Beer, David, Knox, John E., Ma, Ngai Ling, Ehrhardt, Claus, Lim, Siew Pheng, Vasudevan, Subhash G., Keller, Thomas H.
• Format: Article
• Language: English
• Subjects: Aldehydes - antagonists & inhibitors; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding, Competitive; Biological and medical sciences; Boronic Acids - chemistry; Chemistry, Pharmaceutical - methods; Dengue Virus - enzymology; Dengue virus NS3 protease; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - pharmacology; Hydrogen Bonding; Ketones - chemistry; Kinetics; Medical sciences; Models, Chemical; Models, Molecular; Peptide inhibitors; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein Binding; RNA Helicases - antagonists & inhibitors; RNA Helicases - chemistry; Serine Endopeptidases - chemistry; Structure-Activity Relationship; Substrate Specificity; Time Factors; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.09.049

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 μM). 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. 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 μM). 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.