C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease

详细信息    查看全文

• 作者：Mira A. M. Behnam ; Christoph Nitsche ; S茅rgio M. Vechi ; Christian D. Klein
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：5
• 期：9
• 页码：1037-1042
• 全文大小：294K
• ISSN：1948-5875

文摘

Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC₅₀ = 0.6 渭M, K_i = 0.4 渭M). First, a large number of natural and non-natural amino acids were screened at the C-terminal position of the previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH₂). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH₂, IC₅₀ = 13.3 渭M), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC₅₀ = 3.3 渭M). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC₅₀ = 2.5 渭M). This approach led to the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengue protease.

Keywords:

Dengue virus; protease inhibitor; peptide; fragment merging